Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | ClinVar | gnomAD | ESM1b | AlphaMissense | REVEL | PSMutPred | FoldX | Rosetta | Foldetta | PremPS | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | DOI | ||||||||||||||||||||||||||||||||||||||
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| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Score | Prediction | IP RF | SP RF | Prediction | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | PAM250 | PAM120 | Hydropathy Δ | MW Δ | Average | Δ | Δ | StdDev | Δ | StdDev | Secondary | Tertiary bonds | Inside out | GAP-Ras interface | At membrane | No effect | MD Alert | Verdict | Description | |||||
| c.1036G>A | V346M 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V346M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FoldX, whereas the majority of other in silico methods (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, PROVEAN, AlphaMissense‑Optimized, and the SGM‑Consensus score) indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -10.218 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.367 | Likely Benign | 0.1050 | 0.4749 | 0.29 | Likely Benign | 0.1 | 2.52 | Destabilizing | 1.41 | Ambiguous | 0.67 | Ambiguous | -2.72 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.48 | Pathogenic | 0.05 | Affected | 2 | 1 | -2.3 | 32.06 | |||||||||||||||||||||||||
| c.1036G>C | V346L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable predictors and the SGM‑Consensus support a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -8.178 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.384 | Likely Benign | 0.1237 | 0.5348 | 0.05 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.58 | Ambiguous | 0.60 | Ambiguous | -2.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.58 | Pathogenic | 0.09 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1036G>T | V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -8.178 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.386 | Likely Benign | 0.1237 | 0.5348 | 0.05 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.58 | Ambiguous | 0.60 | Ambiguous | -2.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.58 | Pathogenic | 0.09 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1037T>A | V346E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All evaluated in silico predictors classify the change as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic outcome; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic impact. **Conclusion:** The variant is most likely pathogenic based on the unanimous computational evidence, and this assessment is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -14.004 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.720 | Likely Pathogenic | 0.1088 | 0.1568 | 3.30 | Destabilizing | 0.4 | 4.79 | Destabilizing | 4.05 | Destabilizing | 2.13 | Destabilizing | -5.52 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 1.47 | Pathogenic | 0.00 | Affected | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.1037T>C | V346A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346A is reported in gnomAD (6‑33437942‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect are limited to REVEL, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | 6-33437942-T-C | 1 | 6.20e-7 | -8.556 | Likely Pathogenic | 0.856 | Likely Pathogenic | Ambiguous | 0.477 | Likely Benign | 0.3341 | 0.2967 | 2.72 | Destabilizing | 0.2 | 2.73 | Destabilizing | 2.73 | Destabilizing | 1.92 | Destabilizing | -3.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 3.37 | 25 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||
| c.1037T>G | V346G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify it as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports pathogenic. With all evidence converging on a deleterious impact and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -12.779 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.667 | Likely Pathogenic | 0.2378 | 0.2522 | 4.24 | Destabilizing | 0.2 | 4.62 | Destabilizing | 4.43 | Destabilizing | 2.15 | Destabilizing | -6.03 | Deleterious | 0.991 | Probably Damaging | 0.999 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1039A>C | T347P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T347P variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and FATHMM. Three tools (FoldX, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -9.323 | Likely Pathogenic | 0.417 | Ambiguous | Likely Benign | 0.236 | Likely Benign | 0.2000 | 0.5350 | 0.55 | Ambiguous | 0.0 | 0.28 | Likely Benign | 0.42 | Likely Benign | 0.65 | Ambiguous | -2.41 | Neutral | 0.627 | Possibly Damaging | 0.139 | Benign | 1.63 | Pathogenic | 0.12 | Tolerated | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||
| c.1039A>G | T347A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347A is catalogued in gnomAD (ID 6‑33437944‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated. Only FATHMM predicts a pathogenic outcome, while Foldetta, premPS, and Rosetta are inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | 6-33437944-A-G | 9 | 5.58e-6 | -5.858 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.093 | Likely Benign | 0.4032 | 0.4615 | 0.34 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.52 | Ambiguous | 0.70 | Ambiguous | -1.52 | Neutral | 0.031 | Benign | 0.016 | Benign | 1.68 | Pathogenic | 0.42 | Tolerated | 3.37 | 25 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||
| c.1039A>T | T347S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -3.342 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.3205 | 0.4707 | 0.65 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.74 | Ambiguous | -0.10 | Likely Benign | 0.63 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.86 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1040C>A | T347N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347N is listed in ClinVar with an uncertain significance (ClinVar ID 3672484.0) and is present in the gnomAD database (gnomAD ID 6‑33437945‑C‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the collective evidence points to a benign effect, aligning with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | Uncertain | 1 | 6-33437945-C-A | 9 | 5.58e-6 | -5.545 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 0.1070 | 0.4359 | 0.41 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.44 | Likely Benign | -0.06 | Likely Benign | 1.96 | Neutral | 0.001 | Benign | 0.001 | Benign | 1.67 | Pathogenic | 0.60 | Tolerated | 3.37 | 25 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||
| c.1040C>G | T347S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictors indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -3.342 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.054 | Likely Benign | 0.3205 | 0.4707 | 0.65 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.74 | Ambiguous | -0.10 | Likely Benign | 0.63 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.75 | Pathogenic | 0.86 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1040C>T | T347I 2D  3DClick to see structure in 3D Viewer AISynGAP1 T347I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that provide definitive calls cluster into two groups: benign predictions come from REVEL, premPS, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. Tools with inconclusive outputs (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments further split the evidence: AlphaMissense‑Optimized predicts benign, while the SGM consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenic; Foldetta remains uncertain. Consequently, the variant’s pathogenicity is ambiguous, with an equal number of strong benign and pathogenic calls and no consensus from the most reliable methods. The variant is therefore most likely uncertain, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -10.148 | Likely Pathogenic | 0.387 | Ambiguous | Likely Benign | 0.079 | Likely Benign | 0.0885 | 0.6298 | -0.79 | Ambiguous | 0.1 | -0.94 | Ambiguous | -0.87 | Ambiguous | 0.29 | Likely Benign | -3.12 | Deleterious | 0.627 | Possibly Damaging | 0.139 | Benign | 1.70 | Pathogenic | 0.08 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.1042G>A | V348M 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V348M is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that report a clear outcome fall into two groups: benign calls come from REVEL, Foldetta, PROVEAN, and AlphaMissense‑Optimized; pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, ESM1b) give uncertain results, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority. High‑accuracy methods specifically show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus is not available. With four benign and four pathogenic predictions, the evidence is evenly split, providing no definitive direction. Therefore, the variant is not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | Uncertain | 1 | -7.076 | In-Between | 0.546 | Ambiguous | Likely Benign | 0.191 | Likely Benign | 0.0903 | 0.4748 | -1.19 | Ambiguous | 0.1 | 0.72 | Ambiguous | -0.24 | Likely Benign | 0.76 | Ambiguous | -1.62 | Neutral | 0.966 | Probably Damaging | 0.564 | Possibly Damaging | 1.58 | Pathogenic | 0.03 | Affected | 3.37 | 25 | 2 | 1 | -2.3 | 32.06 | 253.8 | -47.4 | -0.3 | 0.1 | 0.2 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val348, located in an anti-parallel β sheet strand (res. Gly341-Pro349), packs against multiple hydrophobic C2 domain residues (e.g., Leu353, Leu323, Leu402). In the variant simulations, the thioether side chain of Met348 can form similar interactions as valine due to its comparable hydrophobic profile. In fact, the thioether group of methionine can even stack favorably with the phenol ring of Tyr363 in the anti-parallel β sheet strand (res. Ala399-Ile411). Overall, the residue swap does not appear to cause negative effects on the protein structure based on the simulations. | |||||||||||||
| c.1042G>C | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.1088 | 0.4953 | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1042G>T | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.1088 | 0.4953 | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1043T>A | V348E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348E is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for V348E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -11.135 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.470 | Likely Benign | 0.1089 | 0.1922 | 2.41 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.31 | Destabilizing | 2.14 | Destabilizing | -5.26 | Deleterious | 0.989 | Probably Damaging | 0.637 | Possibly Damaging | 1.56 | Pathogenic | 0.01 | Affected | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.1043T>C | V348A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further highlight the discrepancy: AlphaMissense‑Optimized predicts a benign effect, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as pathogenic. Taken together, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict ClinVar status, which currently has no entry for V348A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -9.993 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 0.175 | Likely Benign | 0.3223 | 0.2437 | 2.46 | Destabilizing | 0.1 | 3.13 | Destabilizing | 2.80 | Destabilizing | 2.23 | Destabilizing | -3.42 | Deleterious | 0.622 | Possibly Damaging | 0.152 | Benign | 1.59 | Pathogenic | 0.14 | Tolerated | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| c.1043T>G | V348G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the lack of a benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -12.793 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.419 | Likely Benign | 0.2229 | 0.2082 | 3.97 | Destabilizing | 0.2 | 5.70 | Destabilizing | 4.84 | Destabilizing | 2.23 | Destabilizing | -6.18 | Deleterious | 0.637 | Possibly Damaging | 0.989 | Probably Damaging | 1.56 | Pathogenic | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1045C>A | P349T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349T is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM‑Consensus score (which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results are AlphaMissense‑Default, FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -9.736 | Likely Pathogenic | 0.420 | Ambiguous | Likely Benign | 0.246 | Likely Benign | 0.1615 | 0.6238 | 1.37 | Ambiguous | 0.1 | 2.56 | Destabilizing | 1.97 | Ambiguous | 0.76 | Ambiguous | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.57 | Pathogenic | 0.07 | Tolerated | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.1045C>G | P349A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, with the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability or pathogenicity scores are available. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -8.663 | Likely Pathogenic | 0.202 | Likely Benign | Likely Benign | 0.257 | Likely Benign | 0.3789 | 0.5505 | 1.37 | Ambiguous | 0.0 | 1.68 | Ambiguous | 1.53 | Ambiguous | 0.76 | Ambiguous | -6.01 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.1045C>T | P349S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P349S missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, predict a pathogenic effect. Thus, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | Uncertain | 1 | -7.654 | In-Between | 0.217 | Likely Benign | Likely Benign | 0.277 | Likely Benign | 0.3771 | 0.5756 | 1.92 | Ambiguous | 0.1 | 2.28 | Destabilizing | 2.10 | Destabilizing | 0.87 | Ambiguous | -6.13 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.66 | Pathogenic | 0.06 | Tolerated | 3.37 | 25 | 1 | -1 | 0.8 | -10.04 | 194.9 | -18.1 | -0.1 | 0.0 | 0.2 | 0.1 | X | X | Potentially Pathogenic | The cyclic pyrrolidine side chain of Pro349, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), allows the strand to end and make a tight turn before a short α helical section within a loop connecting to another β strand (res. Thr359-Pro364). In the variant simulations, the hydroxyl group of Ser349 forms a hydrogen bond with the backbone amide group of Ala351 in the short helical section. Conversely, the backbone amide group of Ser349 (absent in proline) does not form any intra-protein hydrogen bonds. However, the β strand end connects to the α helical section in a more stable and consistent manner compared to the WT. Although the residue swap does not cause major adverse effects on the protein structure in the simulations, it is possible that the tight turn at the β strand end could not be created during folding without the presence of proline. | ||||||||||||
| c.1046C>A | P349Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 P349Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. High‑accuracy assessments further clarify the variant’s likely effect: AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -10.545 | Likely Pathogenic | 0.508 | Ambiguous | Likely Benign | 0.345 | Likely Benign | 0.1480 | 0.4766 | 0.98 | Ambiguous | 0.1 | 1.87 | Ambiguous | 1.43 | Ambiguous | 0.91 | Ambiguous | -6.40 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.54 | Pathogenic | 0.06 | Tolerated | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||
| c.1046C>G | P349R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for P349R. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -14.001 | Likely Pathogenic | 0.791 | Likely Pathogenic | Ambiguous | 0.335 | Likely Benign | 0.1395 | 0.3009 | 0.99 | Ambiguous | 0.1 | 2.15 | Destabilizing | 1.57 | Ambiguous | 0.93 | Ambiguous | -7.22 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.55 | Pathogenic | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.1046C>T | P349L 2D  AIThe SynGAP1 missense variant P349L is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized, whereas the majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy methods give conflicting results: AlphaMissense‑Optimized reports a benign outcome, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Other stability‑based predictors (FoldX, Rosetta, premPS) are also inconclusive. Overall, the preponderance of evidence from the consensus of multiple in‑silico tools points to a pathogenic effect for P349L. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -11.734 | Likely Pathogenic | 0.650 | Likely Pathogenic | Likely Benign | 0.326 | Likely Benign | 0.2222 | 0.6867 | 0.70 | Ambiguous | 0.6 | 1.17 | Ambiguous | 0.94 | Ambiguous | 0.57 | Ambiguous | -8.04 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.1048G>A | V350M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The remaining tools (FoldX, premPS, ESM1b) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. Taken together, the majority of evidence supports a benign classification. There is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -7.493 | In-Between | 0.273 | Likely Benign | Likely Benign | 0.075 | Likely Benign | 0.1005 | 0.4359 | -0.65 | Ambiguous | 0.1 | 0.40 | Likely Benign | -0.13 | Likely Benign | 0.69 | Ambiguous | -1.95 | Neutral | 0.868 | Possibly Damaging | 0.383 | Benign | 1.63 | Pathogenic | 0.06 | Tolerated | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||
| c.1048G>C | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.042 | Likely Benign | 0.1173 | 0.4958 | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1048G>T | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other tools provide conflicting evidence. Based on the preponderance of predictions, V350L is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.042 | Likely Benign | 0.1173 | 0.4958 | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1049T>A | V350E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effect include REVEL and SIFT, whereas a majority of tools predict pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, Foldetta, and Rosetta. Two tools give inconclusive results: FoldX (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for V350E. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -15.975 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.304 | Likely Benign | 0.1078 | 0.1568 | 1.73 | Ambiguous | 0.2 | 2.61 | Destabilizing | 2.17 | Destabilizing | 1.93 | Destabilizing | -4.67 | Deleterious | 0.976 | Probably Damaging | 0.559 | Possibly Damaging | 1.61 | Pathogenic | 0.08 | Tolerated | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.1049T>C | V350A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V350A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), premPS, PROVEAN, ESM1b, and FATHMM. Stability‑based methods FoldX, Rosetta, and Foldetta give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as unavailable. Overall, the predictions are split, with a slight edge toward pathogenicity from the consensus and high‑accuracy tools. Therefore, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -8.323 | Likely Pathogenic | 0.280 | Likely Benign | Likely Benign | 0.096 | Likely Benign | 0.3207 | 0.2967 | 1.42 | Ambiguous | 0.0 | 1.97 | Ambiguous | 1.70 | Ambiguous | 2.07 | Destabilizing | -2.73 | Deleterious | 0.435 | Benign | 0.115 | Benign | 1.64 | Pathogenic | 0.55 | Tolerated | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| c.1049T>G | V350G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350G lies in the C2 domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumDiv, and AlphaMissense‑Optimized. The remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All predictions are available and consistent. Based on the preponderance of pathogenic calls, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -12.267 | Likely Pathogenic | 0.597 | Likely Pathogenic | Likely Benign | 0.330 | Likely Benign | 0.2316 | 0.2522 | 2.57 | Destabilizing | 0.0 | 4.25 | Destabilizing | 3.41 | Destabilizing | 1.93 | Destabilizing | -5.46 | Deleterious | 0.435 | Benign | 0.920 | Probably Damaging | 1.61 | Pathogenic | 0.02 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1051G>A | A351T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A351T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Uncertain predictions come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as inconclusive. Overall, the majority of evidence supports a benign impact for A351T, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.863 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.1337 | 0.6713 | 0.22 | Likely Benign | 0.0 | 0.80 | Ambiguous | 0.51 | Ambiguous | 0.49 | Likely Benign | -2.42 | Neutral | 0.524 | Possibly Damaging | 0.138 | Benign | 1.71 | Pathogenic | 0.06 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1051G>C | A351P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are Foldetta, PROVEAN, SIFT, FATHMM, and Rosetta. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar reporting; thus the variant is most likely benign rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -6.559 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.051 | Likely Benign | 0.1862 | 0.5472 | -0.89 | Ambiguous | 0.2 | 6.19 | Destabilizing | 2.65 | Destabilizing | 0.62 | Ambiguous | -3.08 | Deleterious | 0.016 | Benign | 0.007 | Benign | 1.67 | Pathogenic | 0.03 | Affected | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||
| c.1051G>T | A351S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (integrating FoldX‑MD and Rosetta)—all report benign or likely benign. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely benign; this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.823 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.016 | Likely Benign | 0.2558 | 0.5334 | 0.24 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.25 | Likely Benign | 0.27 | Likely Benign | -1.42 | Neutral | 0.080 | Benign | 0.023 | Benign | 1.88 | Pathogenic | 0.13 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1052C>A | A351D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A351D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM; AlphaMissense‑Default and ESM1b are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward pathogenic due to two pathogenic and two uncertain calls. Overall, the majority of tools predict a benign outcome, and this does not contradict the lack of ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -7.917 | In-Between | 0.543 | Ambiguous | Likely Benign | 0.114 | Likely Benign | 0.1535 | 0.1386 | -0.02 | Likely Benign | 0.0 | -0.12 | Likely Benign | -0.07 | Likely Benign | 0.49 | Likely Benign | -3.61 | Deleterious | 0.842 | Possibly Damaging | 0.321 | Benign | 1.77 | Pathogenic | 0.11 | Tolerated | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||
| c.1052C>G | A351G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A351G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs two pathogenic), and Foldetta is uncertain. Taken together, the majority of available predictions lean toward a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -4.983 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.2298 | 0.4737 | 0.39 | Likely Benign | 0.0 | 1.04 | Ambiguous | 0.72 | Ambiguous | 0.55 | Ambiguous | -2.53 | Deleterious | 0.688 | Possibly Damaging | 0.138 | Benign | 1.77 | Pathogenic | 0.04 | Affected | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||
| c.1052C>T | A351V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A351V is not reported in ClinVar and is absent from gnomAD. Computational predictions cluster into two groups: benign (REVEL, FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar) and pathogenic (PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, FATHMM, SGM‑Consensus). High‑accuracy tools give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the balance of evidence leans toward a benign effect, but the presence of several pathogenic predictions introduces uncertainty. The variant is most likely benign based on the current computational data, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.362025 | Uncertain | 0.925 | 0.342 | 0.000 | -9.002 | Likely Pathogenic | 0.124 | Likely Benign | Likely Benign | 0.052 | Likely Benign | 0.1140 | 0.6565 | 0.09 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.14 | Likely Benign | 0.29 | Likely Benign | -2.84 | Deleterious | 0.915 | Possibly Damaging | 0.321 | Benign | 1.66 | Pathogenic | 0.03 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1054A>C | T352P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T352P has no ClinVar entry and is not reported in gnomAD. Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, FATHMM, and Rosetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Overall, the balance of evidence favors a benign interpretation; this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -3.562 | Likely Benign | 0.138 | Likely Benign | Likely Benign | 0.159 | Likely Benign | 0.2244 | 0.5968 | 1.04 | Ambiguous | 0.1 | 2.57 | Destabilizing | 1.81 | Ambiguous | 0.51 | Ambiguous | -2.31 | Neutral | 0.627 | Possibly Damaging | 0.196 | Benign | 1.72 | Pathogenic | 0.20 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.1054A>G | T352A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, integrating FoldX‑MD (benign) and Rosetta (uncertain), reports benign stability. Overall, the preponderance of evidence indicates that T352A is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.952 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.032 | Likely Benign | 0.4341 | 0.4938 | 0.12 | Likely Benign | 0.0 | 0.50 | Ambiguous | 0.31 | Likely Benign | 0.45 | Likely Benign | -1.09 | Neutral | 0.031 | Benign | 0.024 | Benign | 1.73 | Pathogenic | 0.29 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.1054A>T | T352S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.670 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.098 | Likely Benign | 0.3583 | 0.4880 | -0.09 | Likely Benign | 0.0 | 0.26 | Likely Benign | 0.09 | Likely Benign | -0.01 | Likely Benign | 0.57 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.81 | Pathogenic | 1.00 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1055C>A | T352N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352N is listed in ClinVar as Benign (ClinVar ID 590151.0) and is present in the gnomAD database (gnomAD ID 6‑33437960‑C‑A). Across the broad panel of in‑silico predictors, 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly report a benign effect, whereas only FATHMM predicts pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also benign. No predictions or stability analyses are missing or inconclusive. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | Likely Benign | 1 | 6-33437960-C-A | 2 | 1.24e-6 | -4.817 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.1311 | 0.4358 | 0.20 | Likely Benign | 0.0 | -0.04 | Likely Benign | 0.08 | Likely Benign | 0.45 | Likely Benign | -0.92 | Neutral | 0.255 | Benign | 0.057 | Benign | 1.75 | Pathogenic | 0.19 | Tolerated | 3.37 | 25 | 0 | 0 | -2.8 | 13.00 | 208.4 | -14.5 | -0.2 | 0.1 | -0.1 | 0.0 | X | Potentially Benign | Thr352 is located in a short α helical section within a loop connecting two β strands (res. Gly341-Pro349, res. Thr359-Pro364) originating from two different anti-parallel β sheets of the C2 domain. In the WT simulations, the side chain hydroxyl and backbone amide groups of Thr354 form hydrogen bonds with the backbone carbonyl group of Pro349 at the end of the preceding β strand. This arrangement likely stabilizes the α helical section and aids in folding, keeping the short secondary structure element intact in the variant simulations. However, the carboxamide group of the Asn352 side chain does not form hydrogen bonds with the backbone carbonyl group of Pro349. Instead, it packs against the cyclic ring and forms hydrogen bonds with the phenol group of the Tyr363 side chain in the other β strand. | |||||||||
| c.1055C>G | T352S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -1.670 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.3583 | 0.4880 | -0.09 | Likely Benign | 0.0 | 0.26 | Likely Benign | 0.09 | Likely Benign | -0.01 | Likely Benign | 0.57 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.81 | Pathogenic | 1.00 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1055C>T | T352I 2D AISynGAP1 T352I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. With seven benign versus five pathogenic predictions and two high‑accuracy benign versus one pathogenic, the evidence leans toward a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -8.023 | Likely Pathogenic | 0.321 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.1009 | 0.6484 | -0.54 | Ambiguous | 0.7 | 0.43 | Likely Benign | -0.06 | Likely Benign | 0.09 | Likely Benign | -3.02 | Deleterious | 0.627 | Possibly Damaging | 0.196 | Benign | 1.67 | Pathogenic | 0.14 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.1057C>A | L353M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar classification; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -6.943 | Likely Benign | 0.206 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.0847 | 0.4080 | 0.10 | Likely Benign | 0.0 | 1.28 | Ambiguous | 0.69 | Ambiguous | 0.60 | Ambiguous | -0.47 | Neutral | 0.744 | Possibly Damaging | 0.289 | Benign | 1.33 | Pathogenic | 0.03 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||
| c.1057C>G | L353V 2D  AISynGAP1 missense variant L353V is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools predicting pathogenicity are FoldX and FATHMM, while Rosetta gives an uncertain result. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the balance of evidence favors a benign effect; this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -2.100 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.1567 | 0.3829 | 3.08 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.28 | Destabilizing | -0.45 | Likely Benign | 1.54 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.46 | Pathogenic | 0.89 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1058T>A | L353Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 L353Q missense variant has no ClinVar entry and is absent from gnomAD. Among in‑silico predictors, only REVEL classifies it as benign, whereas the majority—FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—label it pathogenic. Predictions marked uncertain include Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of pathogenic predictions outweighs the single benign call, and no ClinVar record contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -7.074 | In-Between | 0.884 | Likely Pathogenic | Ambiguous | 0.388 | Likely Benign | 0.1098 | 0.1303 | 2.38 | Destabilizing | 0.2 | 1.41 | Ambiguous | 1.90 | Ambiguous | 2.00 | Destabilizing | -3.56 | Deleterious | 0.947 | Possibly Damaging | 0.556 | Possibly Damaging | 1.30 | Pathogenic | 0.01 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1058T>C | L353P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL predicts benign, whereas FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict pathogenic. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar designation of uncertain significance but leans toward pathogenicity rather than benign. Thus, the variant is most likely pathogenic, and this prediction does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | Uncertain | 1 | -7.913 | In-Between | 0.936 | Likely Pathogenic | Ambiguous | 0.464 | Likely Benign | 0.3582 | 0.1645 | 4.63 | Destabilizing | 0.1 | 10.19 | Destabilizing | 7.41 | Destabilizing | 2.17 | Destabilizing | -3.70 | Deleterious | 0.947 | Possibly Damaging | 0.454 | Possibly Damaging | 1.29 | Pathogenic | 0.02 | Affected | 3.37 | 25 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||
| c.1058T>G | L353R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353R is not reported in ClinVar and is absent from gnomAD. In silico predictors largely agree on a deleterious effect: benign predictions are limited to REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all classify the variant as pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is uncertain, SGM‑Consensus predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction contradicts the ClinVar status, which is currently unreported. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -11.213 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.444 | Likely Benign | 0.1304 | 0.1145 | 3.60 | Destabilizing | 0.5 | 2.48 | Destabilizing | 3.04 | Destabilizing | 1.91 | Destabilizing | -4.15 | Deleterious | 0.947 | Possibly Damaging | 0.454 | Possibly Damaging | 1.33 | Pathogenic | 0.01 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1198G>A | V400M 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V400M is reported in gnomAD (ID 6‑33438103‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, only three tools—polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default—predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX or premPS is available. Overall, the preponderance of predictions, including the high‑accuracy methods, supports a benign classification, which is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | 6-33438103-G-A | 3 | 1.86e-6 | -5.438 | Likely Benign | 0.573 | Likely Pathogenic | Likely Benign | 0.443 | Likely Benign | 0.0851 | 0.4643 | -1.12 | Ambiguous | 0.1 | -0.16 | Likely Benign | -0.64 | Ambiguous | 0.55 | Ambiguous | -1.44 | Neutral | 0.868 | Possibly Damaging | 0.289 | Benign | 5.26 | Benign | 0.01 | Affected | 3.38 | 27 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||
| c.1198G>C | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is listed in ClinVar as Benign (ClinVar ID 1166313.0) and is present in gnomAD (variant ID 6‑33438103‑G‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX, which is treated as unavailable. High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | Benign | 1 | 6-33438103-G-C | 22 | 1.36e-5 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.325 | Likely Benign | 0.1006 | 0.5242 | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | ||||||||
| c.1198G>T | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.325 | Likely Benign | 0.1006 | 0.5242 | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | |||||||||||||
| c.1199T>A | V400E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | Uncertain | 1 | -13.686 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.810 | Likely Pathogenic | 0.1044 | 0.1922 | 3.70 | Destabilizing | 0.2 | 2.46 | Destabilizing | 3.08 | Destabilizing | 2.29 | Destabilizing | -4.88 | Deleterious | 0.920 | Possibly Damaging | 0.335 | Benign | 5.31 | Benign | 0.00 | Affected | 3.38 | 27 | -2 | -2 | -7.7 | 29.98 | 249.1 | -38.8 | -0.1 | 0.1 | 1.0 | 0.0 | X | X | X | Potentially Pathogenic | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). In the variant simulations, the negatively charged carboxylate group of the Glu400 side chain is not suitable for occupying the hydrophobic niche. Consequently, the side chain escapes the center of the C2 domain and interacts with the backbone amide groups of Leu402 in the same β strand and/or Ile269 and Glu270 in a neighboring β strand (res. Arg259-Arg272). This residue swap disrupts the hydrophobic packing and generally has extensive negative effects on the C2 domain structure. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||
| c.1199T>C | V400A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V400A is not reported in ClinVar and is absent from gnomAD. Consensus from standard predictors shows a split: benign calls from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT and AlphaMissense‑Default. Two high‑accuracy tools give a clear signal: AlphaMissense‑Optimized is uncertain, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta also predicts pathogenic. With most evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -7.564 | In-Between | 0.871 | Likely Pathogenic | Ambiguous | 0.479 | Likely Benign | 0.3291 | 0.2767 | 3.14 | Destabilizing | 0.1 | 3.12 | Destabilizing | 3.13 | Destabilizing | 2.29 | Destabilizing | -3.12 | Deleterious | 0.435 | Benign | 0.049 | Benign | 5.32 | Benign | 0.01 | Affected | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||
| c.1199T>G | V400G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V400G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumDiv and FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -11.508 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.819 | Likely Pathogenic | 0.2296 | 0.2522 | 4.84 | Destabilizing | 0.1 | 5.40 | Destabilizing | 5.12 | Destabilizing | 2.40 | Destabilizing | -5.70 | Deleterious | 0.335 | Benign | 0.920 | Probably Damaging | 5.27 | Benign | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1201C>G | R401G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.314870 | Structured | 0.424277 | Uncertain | 0.961 | 0.419 | 0.000 | -13.353 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.741 | Likely Pathogenic | 0.3549 | 0.2866 | 3.06 | Destabilizing | 0.2 | 4.31 | Destabilizing | 3.69 | Destabilizing | 1.01 | Destabilizing | -6.45 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.45 | Benign | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.1201C>T | R401W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401W is listed in gnomAD (ID 6‑33438106‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions are returned by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Only FATHMM predicts a benign outcome; all other tools are either pathogenic or inconclusive. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Taken together, the overwhelming majority of predictions support a pathogenic effect, and this conclusion is not contradicted by ClinVar data, which currently contains no classification for the variant. Based on the aggregate predictions, the variant is most likely pathogenic, and this is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.314870 | Structured | 0.424277 | Uncertain | 0.961 | 0.419 | 0.000 | 6-33438106-C-T | 2 | 1.24e-6 | -10.712 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.711 | Likely Pathogenic | 0.1252 | 0.3791 | 1.59 | Ambiguous | 0.2 | 1.04 | Ambiguous | 1.32 | Ambiguous | 0.73 | Ambiguous | -7.34 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 5.40 | Benign | 0.00 | Affected | 3.38 | 27 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||
| c.1202G>A | R401Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438107‑G‑A). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic prediction: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic,” and Foldetta’s stability assessment is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.314870 | Structured | 0.424277 | Uncertain | 0.961 | 0.419 | 0.000 | Uncertain | 1 | 6-33438107-G-A | -11.213 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.780 | Likely Pathogenic | 0.3234 | 0.2269 | 0.96 | Ambiguous | 0.1 | 1.50 | Ambiguous | 1.23 | Ambiguous | 1.20 | Destabilizing | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.978 | Probably Damaging | 5.47 | Benign | 0.04 | Affected | 3.38 | 27 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||
| c.1202G>C | R401P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.314870 | Structured | 0.424277 | Uncertain | 0.961 | 0.419 | 0.000 | -14.090 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.892 | Likely Pathogenic | 0.2265 | 0.4064 | 9.69 | Destabilizing | 0.3 | 8.07 | Destabilizing | 8.88 | Destabilizing | 0.77 | Ambiguous | -6.45 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.42 | Benign | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1202G>T | R401L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R401L is not reported in ClinVar and is present in gnomAD (ID 6‑33438107‑G‑T). Prediction tools that classify the variant as benign include Rosetta, FATHMM, and premPS, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) indicate a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX alone is available. Based on the preponderance of pathogenic predictions and the corroborating high‑accuracy tools, R401L is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.314870 | Structured | 0.424277 | Uncertain | 0.961 | 0.419 | 0.000 | 6-33438107-G-T | 1 | 6.20e-7 | -12.280 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.858 | Likely Pathogenic | 0.1972 | 0.4263 | -1.52 | Ambiguous | 0.1 | -0.23 | Likely Benign | -0.88 | Ambiguous | 0.22 | Likely Benign | -6.42 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.44 | Benign | 0.02 | Affected | 3.38 | 27 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||
| c.1204C>A | L402M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402M is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -6.991 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.071 | Likely Benign | 0.1064 | 0.4095 | 0.12 | Likely Benign | 0.0 | 1.33 | Ambiguous | 0.73 | Ambiguous | 0.80 | Ambiguous | -0.99 | Neutral | 0.994 | Probably Damaging | 0.938 | Probably Damaging | 3.73 | Benign | 0.02 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||
| c.1204C>G | L402V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a benign outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is therefore not considered evidence for pathogenicity. In summary, all available predictions support a benign classification for the L402V variant, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -3.467 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.203 | Likely Benign | 0.1807 | 0.3657 | 1.91 | Ambiguous | 0.1 | 0.78 | Ambiguous | 1.35 | Ambiguous | -0.11 | Likely Benign | 0.18 | Neutral | 0.004 | Benign | 0.004 | Benign | 4.01 | Benign | 0.29 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1205T>A | L402Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -13.403 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.523 | Likely Pathogenic | 0.1384 | 0.1173 | 2.93 | Destabilizing | 0.0 | 2.55 | Destabilizing | 2.74 | Destabilizing | 2.09 | Destabilizing | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.957 | Probably Damaging | 3.69 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1205T>C | L402P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L402P is not reported in ClinVar and is absent from gnomAD. Consensus among in‑silico predictors is overwhelmingly pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, whereas only FATHMM predicts a benign outcome. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the evidence strongly supports a pathogenic classification, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -12.030 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.616 | Likely Pathogenic | 0.3628 | 0.1874 | 7.40 | Destabilizing | 0.1 | 5.82 | Destabilizing | 6.61 | Destabilizing | 2.22 | Destabilizing | -4.80 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 3.68 | Benign | 0.01 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1205T>G | L402R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402R is listed in ClinVar as Pathogenic (ClinVar ID 559657.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the overwhelming agreement among pathogenic predictions and the concordance with ClinVar, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | Likely Pathogenic | 1 | -13.800 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.522 | Likely Pathogenic | 0.1467 | 0.1173 | 4.10 | Destabilizing | 0.2 | 3.82 | Destabilizing | 3.96 | Destabilizing | 2.24 | Destabilizing | -4.69 | Deleterious | 0.967 | Probably Damaging | 0.459 | Possibly Damaging | 3.69 | Benign | 0.00 | Affected | 3.38 | 28 | -3 | -2 | -8.3 | 43.03 | 259.5 | -55.4 | 0.0 | 0.0 | 1.4 | 0.0 | X | X | X | Potentially Pathogenic | The iso-butyl side chain of Leu402, located in an anti-parallel β sheet strand (res. Ala399-Ile411), packs with residues inside the hydrophobic core of the C2 domain (e.g., Ile268, Ala404, Leu266, Val400). In the variant simulations, the positively charged guanidinium group of the Arg402 side chain is not suitable for the hydrophobic niche. Consequently, the side chain moves outward from the hydrophobic C2 domain core and stacks with the phenol ring of Tyr363 or forms H-bonds with the carboxamide group of the Gln361 side chain in the β sheet strand (res. Thr359-Tyr364). This movement induces extensive negative effects on the C2 domain structure. | ||||||||||
| c.1207A>C | K403Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K403Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. The premPS assessment is uncertain and does not influence the overall consensus. High‑accuracy analyses show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -12.479 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.376 | Likely Benign | 0.4405 | 0.1954 | 0.36 | Likely Benign | 0.0 | 0.27 | Likely Benign | 0.32 | Likely Benign | 0.70 | Ambiguous | -3.59 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.76 | Benign | 0.01 | Affected | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.1207A>G | K403E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K403E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for K403E, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -15.279 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.445 | Likely Benign | 0.3650 | 0.1715 | 1.01 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.90 | Ambiguous | 0.70 | Ambiguous | -3.62 | Deleterious | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 3.79 | Benign | 0.04 | Affected | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1208A>C | K403T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K403T missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also uncertain. Overall, the consensus of the majority of tools indicates a pathogenic effect. This conclusion is not contradicted by ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -13.135 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.522 | Likely Pathogenic | 0.1861 | 0.4230 | 1.41 | Ambiguous | 0.1 | 0.59 | Ambiguous | 1.00 | Ambiguous | 0.67 | Ambiguous | -5.43 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.73 | Benign | 0.01 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1208A>G | K403R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K403R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The remaining tools—FoldX, ESM1b, and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a tie, and Foldetta also predicts benign. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -7.362 | In-Between | 0.355 | Ambiguous | Likely Benign | 0.335 | Likely Benign | 0.4834 | 0.1861 | -0.78 | Ambiguous | 0.1 | 0.23 | Likely Benign | -0.28 | Likely Benign | 0.41 | Likely Benign | -2.56 | Deleterious | 0.983 | Probably Damaging | 0.926 | Probably Damaging | 3.91 | Benign | 0.15 | Tolerated | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||
| c.1208A>T | K403I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, premPS, and FATHMM, while the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (nine pathogenic vs. five benign) and the high‑accuracy tools lean toward a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -15.239 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.519 | Likely Pathogenic | 0.1223 | 0.4141 | 0.17 | Likely Benign | 0.1 | -0.46 | Likely Benign | -0.15 | Likely Benign | 0.36 | Likely Benign | -7.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.70 | Benign | 0.00 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.1209A>C | K403N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. Predictions from FoldX, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -10.913 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.201 | Likely Benign | 0.3374 | 0.2492 | 1.87 | Ambiguous | 0.1 | 0.41 | Likely Benign | 1.14 | Ambiguous | 0.74 | Ambiguous | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.73 | Benign | 0.05 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1209A>T | K403N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K403N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict a pathogenic impact. Predictions from FoldX, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -10.913 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.201 | Likely Benign | 0.3374 | 0.2492 | 1.87 | Ambiguous | 0.1 | 0.41 | Likely Benign | 1.14 | Ambiguous | 0.74 | Ambiguous | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.73 | Benign | 0.05 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1210G>A | A404T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FoldX and premPS are inconclusive, so they are treated as unavailable. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta) is benign. Overall, the evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -6.674 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.1710 | 0.7367 | 0.74 | Ambiguous | 0.1 | -0.01 | Likely Benign | 0.37 | Likely Benign | 0.56 | Ambiguous | -1.74 | Neutral | 0.049 | Benign | 0.011 | Benign | 4.12 | Benign | 0.09 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1210G>C | A404P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A404P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, both polyPhen‑2 versions, and FATHMM, while pathogenic calls arise from FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -11.819 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.227 | Likely Benign | 0.2271 | 0.6366 | 3.03 | Destabilizing | 0.1 | 0.24 | Likely Benign | 1.64 | Ambiguous | 1.17 | Destabilizing | -3.16 | Deleterious | 0.433 | Benign | 0.080 | Benign | 4.02 | Benign | 0.03 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1210G>T | A404S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign effect. No inconclusive or missing predictions are present. Based on the unanimous benign predictions and the lack of ClinVar evidence, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -1.937 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.078 | Likely Benign | 0.2970 | 0.6178 | 0.13 | Likely Benign | 0.0 | 0.83 | Ambiguous | 0.48 | Likely Benign | 0.28 | Likely Benign | -0.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.18 | Benign | 0.22 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1211C>A | A404E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -13.639 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.163 | Likely Benign | 0.1423 | 0.2383 | 2.16 | Destabilizing | 0.1 | 3.04 | Destabilizing | 2.60 | Destabilizing | 1.51 | Destabilizing | -2.77 | Deleterious | 0.179 | Benign | 0.033 | Benign | 4.02 | Benign | 0.02 | Affected | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||
| c.1211C>G | A404G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A404G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS and SIFT. FoldX, Rosetta, and Foldetta give uncertain or inconclusive results and are treated as unavailable. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the majority of evidence points to a benign impact for A404G, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | -5.277 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.2370 | 0.5054 | 0.92 | Ambiguous | 0.0 | 1.88 | Ambiguous | 1.40 | Ambiguous | 1.18 | Destabilizing | -2.34 | Neutral | 0.045 | Benign | 0.013 | Benign | 4.03 | Benign | 0.00 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1211C>T | A404V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A404V missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438116‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and ESM1b. Four tools (FoldX, Rosetta, AlphaMissense‑Default, Foldetta) give uncertain or inconclusive results. High‑accuracy methods give mixed evidence: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of predictions lean toward a benign impact, though a key consensus method suggests pathogenicity, leaving the variant’s effect unresolved. **The variant is most likely benign based on the prevailing predictions, and this assessment does not contradict ClinVar status, as no ClinVar classification exists.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.232838 | Structured | 0.415505 | Uncertain | 0.965 | 0.355 | 0.000 | 6-33438116-C-T | 1 | 6.20e-7 | -8.219 | Likely Pathogenic | 0.343 | Ambiguous | Likely Benign | 0.118 | Likely Benign | 0.1288 | 0.6842 | 0.56 | Ambiguous | 0.3 | -1.55 | Ambiguous | -0.50 | Ambiguous | -0.05 | Likely Benign | -2.96 | Deleterious | 0.345 | Benign | 0.018 | Benign | 4.20 | Benign | 0.47 | Tolerated | 3.38 | 28 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||
| c.1213C>A | R405S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts Pathogenic. Taken together, the overwhelming majority of evidence indicates that R405S is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.326 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.405 | Likely Benign | 0.2829 | 0.4646 | 2.66 | Destabilizing | 0.5 | 2.08 | Destabilizing | 2.37 | Destabilizing | 1.22 | Destabilizing | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.67 | Benign | 0.05 | Affected | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| c.1213C>G | R405G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.836 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.419 | Likely Benign | 0.3381 | 0.4139 | 3.22 | Destabilizing | 0.5 | 3.26 | Destabilizing | 3.24 | Destabilizing | 1.38 | Destabilizing | -6.35 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.63 | Benign | 0.01 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.1213C>T | R405C 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R405C is listed in ClinVar with an uncertain significance (ClinVar ID 1185858.0) and is present in gnomAD (ID 6‑33438118‑C‑T). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually return uncertain results. Overall, the balance of evidence favors a pathogenic interpretation, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Conflicting | 2 | 6-33438118-C-T | 6 | 3.72e-6 | -9.206 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.427 | Likely Benign | 0.3227 | 0.3964 | 0.72 | Ambiguous | 0.1 | 1.51 | Ambiguous | 1.12 | Ambiguous | 1.21 | Destabilizing | -7.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.61 | Benign | 0.02 | Affected | 3.38 | 28 | -4 | -3 | 7.0 | -53.05 | 221.3 | 82.6 | -0.1 | 0.0 | -0.2 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Ala399-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the thiol-containing side chain of Cys405 is neutral and smaller compared to the arginine side chain. The lack of Arg405-Phe358 stacking affects the loop structure, causing it to assume a β strand form—an effect that could be exacerbated during protein folding. Moreover, the inability of Cys405 to form a salt bridge with Glu446 could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | ||||||||
| c.1214G>A | R405H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R405H is listed in ClinVar with an uncertain significance (ClinVar ID 863440.0) and is present in gnomAD (variant ID 6‑33438119‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized reports a benign change, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the preponderance of evidence indicates that R405H is most likely pathogenic, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Conflicting | 2 | 6-33438119-G-A | 4 | 2.48e-6 | -9.081 | Likely Pathogenic | 0.706 | Likely Pathogenic | Likely Benign | 0.371 | Likely Benign | 0.3395 | 0.2363 | 2.79 | Destabilizing | 0.6 | 1.85 | Ambiguous | 2.32 | Destabilizing | 1.26 | Destabilizing | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.65 | Benign | 0.01 | Affected | 3.38 | 28 | 2 | 0 | 1.3 | -19.05 | 214.0 | 102.2 | -0.1 | 0.0 | -0.7 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Pro398-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the imidazole ring of His405 does not stack with the aromatic ring of Phe358 nor form any lasting H-bonds with the loop residues. The imidazole ring of His405 (neutral and epsilon protonated in the simulations) is unable to form a salt bridge with Glu446, which could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | |||||||||
| c.1214G>C | R405P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies it as pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Uncertain | 1 | -14.206 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 0.2140 | 0.5138 | 3.11 | Destabilizing | 0.3 | 5.19 | Destabilizing | 4.15 | Destabilizing | 1.26 | Destabilizing | -6.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.62 | Benign | 0.01 | Affected | 3.38 | 28 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||
| c.1214G>T | R405L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R405L missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are Rosetta and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) indicate a pathogenic or likely pathogenic impact. Uncertain results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta providing an inconclusive stability prediction. Overall, the preponderance of evidence points to a pathogenic effect for R405L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.576 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.512 | Likely Pathogenic | 0.2126 | 0.5555 | 1.43 | Ambiguous | 0.7 | 0.40 | Likely Benign | 0.92 | Ambiguous | 0.72 | Ambiguous | -6.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.64 | Benign | 0.01 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1216T>A | Y406N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates pathogenicity. Taken together, the preponderance of evidence points to a pathogenic effect for Y406N, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -13.206 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.288 | Likely Benign | 0.2532 | 0.1071 | 2.90 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.89 | Destabilizing | 1.58 | Destabilizing | -7.11 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 3.78 | Benign | 0.02 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.1216T>C | Y406H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y406H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently classify the substitution as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the preponderance of evidence indicates that Y406H is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -9.015 | Likely Pathogenic | 0.858 | Likely Pathogenic | Ambiguous | 0.239 | Likely Benign | 0.2666 | 0.0811 | 2.13 | Destabilizing | 0.1 | 2.15 | Destabilizing | 2.14 | Destabilizing | 1.03 | Destabilizing | -4.21 | Deleterious | 0.997 | Probably Damaging | 0.966 | Probably Damaging | 3.80 | Benign | 0.03 | Affected | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.1216T>G | Y406D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. In contrast, the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” while premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -14.832 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.347 | Likely Benign | 0.4439 | 0.0903 | 3.82 | Destabilizing | 0.3 | 4.28 | Destabilizing | 4.05 | Destabilizing | 0.98 | Ambiguous | -7.64 | Deleterious | 0.999 | Probably Damaging | 0.950 | Probably Damaging | 3.77 | Benign | 0.01 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.1217A>C | Y406S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FoldX, Rosetta, premPS, and Foldetta all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -12.014 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | 0.4719 | 0.2817 | 3.51 | Destabilizing | 0.3 | 4.08 | Destabilizing | 3.80 | Destabilizing | 1.40 | Destabilizing | -6.72 | Deleterious | 0.991 | Probably Damaging | 0.886 | Possibly Damaging | 3.80 | Benign | 0.06 | Tolerated | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.1217A>G | Y406C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome, and the Foldetta stability assessment (combining FoldX‑MD and Rosetta) predicts a destabilizing, pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while both SGM‑Consensus and Foldetta are pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for Y406C, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -9.954 | Likely Pathogenic | 0.810 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | 0.3026 | 0.2861 | 2.47 | Destabilizing | 0.2 | 3.22 | Destabilizing | 2.85 | Destabilizing | 1.27 | Destabilizing | -6.72 | Deleterious | 0.998 | Probably Damaging | 0.851 | Possibly Damaging | 3.78 | Benign | 0.01 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.1217A>T | Y406F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -3.427 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.2673 | 0.3952 | -0.01 | Likely Benign | 0.2 | 0.40 | Likely Benign | 0.20 | Likely Benign | 0.15 | Likely Benign | -0.93 | Neutral | 0.002 | Benign | 0.002 | Benign | 3.96 | Benign | 0.31 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||
| c.1219C>A | Q407K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools, FoldX and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is unavailable because FoldX is uncertain and Rosetta alone is benign. Overall, the majority of evidence points to a pathogenic impact for Q407K. This conclusion is not contradicted by ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -14.893 | Likely Pathogenic | 0.765 | Likely Pathogenic | Likely Benign | 0.246 | Likely Benign | 0.1656 | 0.3504 | 0.61 | Ambiguous | 0.1 | 0.19 | Likely Benign | 0.40 | Likely Benign | 0.93 | Ambiguous | -3.42 | Deleterious | 0.863 | Possibly Damaging | 0.773 | Possibly Damaging | 3.96 | Benign | 0.07 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||
| c.1219C>G | Q407E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools and the SGM Consensus support a pathogenic classification, while a minority predict benign. No ClinVar entry exists to contradict these predictions. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -12.631 | Likely Pathogenic | 0.466 | Ambiguous | Likely Benign | 0.243 | Likely Benign | 0.1199 | 0.2000 | 0.50 | Ambiguous | 0.1 | 1.68 | Ambiguous | 1.09 | Ambiguous | 1.30 | Destabilizing | -2.66 | Deleterious | 0.989 | Probably Damaging | 0.930 | Probably Damaging | 3.96 | Benign | 0.03 | Affected | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.1220A>C | Q407P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is uncertain and is not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -13.578 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.515 | Likely Pathogenic | 0.1786 | 0.4352 | 3.04 | Destabilizing | 0.5 | 2.07 | Destabilizing | 2.56 | Destabilizing | 0.88 | Ambiguous | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.88 | Benign | 0.02 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.1220A>G | Q407R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With two of the three high‑accuracy methods indicating benign and the remaining one pathogenic, the overall evidence leans toward a benign classification. This conclusion does not contradict ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -13.263 | Likely Pathogenic | 0.693 | Likely Pathogenic | Likely Benign | 0.340 | Likely Benign | 0.1347 | 0.1596 | 0.15 | Likely Benign | 0.2 | 0.09 | Likely Benign | 0.12 | Likely Benign | 0.65 | Ambiguous | -3.52 | Deleterious | 0.909 | Possibly Damaging | 0.889 | Possibly Damaging | 4.02 | Benign | 0.17 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||
| c.1220A>T | Q407L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Four tools are uncertain (AlphaMissense‑Default, FoldX, Rosetta, Foldetta). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, more tools predict pathogenicity than benign, and the high‑accuracy consensus leans pathogenic. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -12.730 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | 0.359 | Likely Benign | 0.0585 | 0.4977 | -0.65 | Ambiguous | 0.2 | -0.69 | Ambiguous | -0.67 | Ambiguous | 0.35 | Likely Benign | -6.32 | Deleterious | 0.939 | Possibly Damaging | 0.838 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||
| c.1221G>C | Q407H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407H (C2 domain) has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -10.526 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.206 | Likely Benign | 0.1205 | 0.3154 | 0.59 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.60 | Ambiguous | 1.10 | Destabilizing | -4.51 | Deleterious | 0.982 | Probably Damaging | 0.947 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 3.38 | 28 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||
| c.1221G>T | Q407H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q407H is listed in ClinVar with an uncertain significance (ClinVar ID 2772184.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked as uncertain include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for Q407H. This conclusion does not conflict with the ClinVar designation of uncertain significance, which remains unresolved pending further evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | Uncertain | 1 | -10.526 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.206 | Likely Benign | 0.1205 | 0.3154 | 0.59 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.60 | Ambiguous | 1.10 | Destabilizing | -4.51 | Deleterious | 0.982 | Probably Damaging | 0.947 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 3.38 | 28 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||
| c.1222A>C | T408P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX, premPS, and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and thus unavailable; Foldetta remains uncertain. Overall, the majority of available predictions (six pathogenic vs. four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -10.384 | Likely Pathogenic | 0.230 | Likely Benign | Likely Benign | 0.323 | Likely Benign | 0.1985 | 0.5779 | 1.08 | Ambiguous | 0.3 | 2.27 | Destabilizing | 1.68 | Ambiguous | 0.73 | Ambiguous | -4.19 | Deleterious | 0.998 | Probably Damaging | 0.963 | Probably Damaging | 4.07 | Benign | 0.05 | Affected | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||
| c.1222A>G | T408A 2D AISynGAP1 missense variant T408A is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, a protein‑folding stability method, also predicts benign. Overall, the balance of evidence favors a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | Uncertain | 1 | -8.304 | Likely Pathogenic | 0.114 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.3970 | 0.4674 | 0.37 | Likely Benign | 0.6 | -0.06 | Likely Benign | 0.16 | Likely Benign | 0.72 | Ambiguous | -3.07 | Deleterious | 0.540 | Possibly Damaging | 0.131 | Benign | 4.16 | Benign | 0.14 | Tolerated | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||
| c.1222A>T | T408S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408S is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, FoldX, Rosetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Consequently, the variant is most likely benign, and this prediction does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -6.277 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.3256 | 0.4767 | 0.10 | Likely Benign | 0.0 | 0.39 | Likely Benign | 0.25 | Likely Benign | 0.18 | Likely Benign | -1.48 | Neutral | 0.182 | Benign | 0.127 | Benign | 4.24 | Benign | 0.21 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1223C>A | T408K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408K is not listed in ClinVar (ClinVar ID None) and has no reported allele in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, SIFT, FATHMM, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default; premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -11.841 | Likely Pathogenic | 0.756 | Likely Pathogenic | Likely Benign | 0.131 | Likely Benign | 0.1205 | 0.3384 | -0.44 | Likely Benign | 0.2 | 0.14 | Likely Benign | -0.15 | Likely Benign | 0.88 | Ambiguous | -3.79 | Deleterious | 0.851 | Possibly Damaging | 0.163 | Benign | 4.17 | Benign | 0.15 | Tolerated | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||
| c.1223C>G | T408R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T408R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. With six benign versus seven pathogenic calls overall, the evidence is mixed, but the presence of two independent high‑accuracy benign predictions and the lack of ClinVar or gnomAD support suggests the variant is most likely benign, and this does not contradict any existing clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | -12.075 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.138 | Likely Benign | 0.1029 | 0.3180 | -0.48 | Likely Benign | 0.1 | -0.24 | Likely Benign | -0.36 | Likely Benign | 0.79 | Ambiguous | -4.06 | Deleterious | 0.991 | Probably Damaging | 0.645 | Possibly Damaging | 4.12 | Benign | 0.15 | Tolerated | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||
| c.1223C>T | T408I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T408I missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438128‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Tools with uncertain or mixed outputs are AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | 6-33438128-C-T | 1 | 6.19e-7 | -10.023 | Likely Pathogenic | 0.542 | Ambiguous | Likely Benign | 0.131 | Likely Benign | 0.0905 | 0.6700 | -0.16 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.42 | Likely Benign | 0.38 | Likely Benign | -4.53 | Deleterious | 0.976 | Probably Damaging | 0.607 | Possibly Damaging | 4.08 | Benign | 0.05 | Affected | 3.38 | 28 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||
| c.1225A>C | M409L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The only inconclusive result is from premPS, which is marked uncertain and does not influence the overall benign consensus. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -6.809 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.199 | Likely Benign | 0.1299 | 0.4411 | -0.04 | Likely Benign | 0.2 | -0.08 | Likely Benign | -0.06 | Likely Benign | 0.51 | Ambiguous | -0.84 | Neutral | 0.206 | Benign | 0.324 | Benign | 4.21 | Benign | 0.57 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1225A>G | M409V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409V is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors indicates a benign effect: REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports benign. No conflicting evidence is present. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -4.109 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.163 | Likely Benign | 0.2706 | 0.4286 | 1.13 | Ambiguous | 0.2 | -0.25 | Likely Benign | 0.44 | Likely Benign | 0.37 | Likely Benign | -0.76 | Neutral | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 4.26 | Benign | 1.00 | Tolerated | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||
| c.1225A>T | M409L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The only inconclusive result is premPS, which is listed as uncertain and does not influence the overall assessment. High‑accuracy methods confirm the benign prediction: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also classifies it as benign. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -6.809 | Likely Benign | 0.286 | Likely Benign | Likely Benign | 0.199 | Likely Benign | 0.1299 | 0.4411 | -0.04 | Likely Benign | 0.2 | -0.08 | Likely Benign | -0.06 | Likely Benign | 0.51 | Ambiguous | -0.84 | Neutral | 0.206 | Benign | 0.324 | Benign | 4.21 | Benign | 0.57 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1226T>A | M409K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409K has no ClinVar record and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, SIFT, and FATHMM, while pathogenic calls arise from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -13.618 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.490 | Likely Benign | 0.1318 | 0.0656 | 0.93 | Ambiguous | 0.3 | 0.29 | Likely Benign | 0.61 | Ambiguous | 1.45 | Destabilizing | -4.26 | Deleterious | 0.769 | Possibly Damaging | 0.750 | Possibly Damaging | 4.18 | Benign | 0.40 | Tolerated | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||
| c.1226T>C | M409T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic outcome; Foldetta remains inconclusive. Overall, the majority of evidence, including the SGM‑Consensus, points to a pathogenic impact for M409T. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -9.194 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 0.262 | Likely Benign | 0.1835 | 0.2391 | 1.41 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.95 | Ambiguous | 0.96 | Ambiguous | -3.18 | Deleterious | 0.987 | Probably Damaging | 0.945 | Probably Damaging | 4.17 | Benign | 0.45 | Tolerated | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||
| c.1226T>G | M409R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409R is not reported in ClinVar and is present in gnomAD (ID 6‑33438131‑T‑G). Functional prediction tools cluster into two groups: benign (REVEL, SIFT, FATHMM, Rosetta) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Three tools give uncertain results (FoldX, Foldetta, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the balance of evidence favors a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | 6-33438131-T-G | -12.795 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.485 | Likely Benign | 0.1537 | 0.0957 | 1.47 | Ambiguous | 0.4 | 0.44 | Likely Benign | 0.96 | Ambiguous | 1.30 | Destabilizing | -4.39 | Deleterious | 0.877 | Possibly Damaging | 0.807 | Possibly Damaging | 4.15 | Benign | 0.27 | Tolerated | 3.38 | 28 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||
| c.1227G>A | M409I 2D  AISynGAP1 missense variant M409I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default). High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a benign effect. FoldX and Rosetta individually give uncertain results and are treated as unavailable. Overall, the majority of reliable predictors indicate a benign impact for M409I. Thus, the variant is most likely benign, and this conclusion does not contradict the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -3.735 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | 0.1105 | 0.3358 | 0.59 | Ambiguous | 0.8 | -0.79 | Ambiguous | -0.10 | Likely Benign | 0.36 | Likely Benign | -0.58 | Neutral | 0.579 | Possibly Damaging | 0.663 | Possibly Damaging | 4.22 | Benign | 0.92 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||
| c.1227G>C | M409I 2D AISynGAP1 missense variant M409I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default). High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a benign effect. FoldX and Rosetta individually give uncertain results and are treated as unavailable. Overall, the majority of reliable predictors indicate a benign impact for M409I, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -3.735 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | 0.1105 | 0.3358 | 0.59 | Ambiguous | 0.8 | -0.79 | Ambiguous | -0.10 | Likely Benign | 0.36 | Likely Benign | -0.58 | Neutral | 0.579 | Possibly Damaging | 0.663 | Possibly Damaging | 4.22 | Benign | 0.92 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||
| c.1227G>T | M409I 2D AISynGAP1 missense variant M409I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default). High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a benign effect. FoldX and Rosetta individually give uncertain results and are treated as unavailable. Overall, the majority of reliable predictors indicate a benign impact for M409I, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -3.735 | Likely Benign | 0.598 | Likely Pathogenic | Likely Benign | 0.162 | Likely Benign | 0.1105 | 0.3358 | 0.59 | Ambiguous | 0.8 | -0.79 | Ambiguous | -0.10 | Likely Benign | 0.36 | Likely Benign | -0.58 | Neutral | 0.579 | Possibly Damaging | 0.663 | Possibly Damaging | 4.22 | Benign | 0.92 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||
| c.1228A>C | S410R 2D  3DClick to see structure in 3D Viewer AIClinVar contains no record for the SynGAP1 S410R variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta predicts a benign impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Taken together, the majority of evidence points to a benign outcome. This conclusion does not contradict ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -8.203 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.242 | Likely Benign | 0.0955 | 0.3927 | -0.67 | Ambiguous | 0.2 | 0.56 | Ambiguous | -0.06 | Likely Benign | 0.62 | Ambiguous | -2.47 | Neutral | 0.871 | Possibly Damaging | 0.298 | Benign | 4.20 | Benign | 0.40 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1228A>G | S410G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -7.147 | In-Between | 0.137 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.2651 | 0.5143 | 0.58 | Ambiguous | 0.1 | 1.33 | Ambiguous | 0.96 | Ambiguous | 0.85 | Ambiguous | -2.54 | Deleterious | 0.952 | Possibly Damaging | 0.145 | Benign | 4.13 | Benign | 0.19 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||
| c.1228A>T | S410C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict it as pathogenic are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -7.552 | In-Between | 0.144 | Likely Benign | Likely Benign | 0.230 | Likely Benign | 0.1041 | 0.6543 | -0.24 | Likely Benign | 0.1 | 0.31 | Likely Benign | 0.04 | Likely Benign | 0.22 | Likely Benign | -3.10 | Deleterious | 0.993 | Probably Damaging | 0.536 | Possibly Damaging | 4.12 | Benign | 0.11 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||
| c.1229G>A | S410N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410N is predicted to be benign by all evaluated in‑silico tools. Consensus predictors (REVEL, SIFT, polyPhen‑2 HumDiv/HumVar, PROVEAN, premPS, FoldX, Rosetta, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly report a benign effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies it as “Likely Benign.” High‑accuracy assessments likewise support a benign outcome: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a benign effect. ClinVar contains no entry for this variant, and it is not present in gnomAD. Based on the collective predictions, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -2.901 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.1310 | 0.5471 | -0.16 | Likely Benign | 0.1 | -0.16 | Likely Benign | -0.16 | Likely Benign | 0.38 | Likely Benign | -0.91 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.18 | Tolerated | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||
| c.1229G>C | S410T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410T has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Foldetta, SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and premPS. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. **Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -6.559 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 0.1371 | 0.7159 | -0.32 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.42 | Likely Benign | 0.00 | Likely Benign | -0.78 | Neutral | 0.080 | Benign | 0.026 | Benign | 4.24 | Benign | 0.84 | Tolerated | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| c.1229G>T | S410I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are uncertain or inconclusive are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic, and Foldetta remains uncertain. Overall, the majority of tools suggest a benign impact, but the high‑accuracy consensus indicates potential pathogenicity, leaving the variant’s effect ambiguous. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -9.383 | Likely Pathogenic | 0.432 | Ambiguous | Likely Benign | 0.114 | Likely Benign | 0.0965 | 0.6579 | -1.08 | Ambiguous | 0.2 | -0.36 | Likely Benign | -0.72 | Ambiguous | -0.41 | Likely Benign | -3.21 | Deleterious | 0.993 | Probably Damaging | 0.589 | Possibly Damaging | 4.15 | Benign | 0.21 | Tolerated | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||
| c.1230C>A | S410R 2D 3DClick to see structure in 3D Viewer AIClinVar contains no record for the SynGAP1 S410R variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta predicts a benign impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Taken together, the majority of evidence points to a benign outcome. This conclusion does not contradict ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -8.203 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.148 | Likely Benign | 0.0955 | 0.3927 | -0.67 | Ambiguous | 0.2 | 0.56 | Ambiguous | -0.06 | Likely Benign | 0.62 | Ambiguous | -2.47 | Neutral | 0.871 | Possibly Damaging | 0.298 | Benign | 4.20 | Benign | 0.40 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1230C>G | S410R 2D 3DClick to see structure in 3D Viewer AIClinVar contains no record for the SynGAP1 S410R variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta predicts a benign impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Taken together, the majority of evidence points to a benign outcome. This conclusion does not contradict ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -8.203 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | 0.0955 | 0.3927 | -0.67 | Ambiguous | 0.2 | 0.56 | Ambiguous | -0.06 | Likely Benign | 0.62 | Ambiguous | -2.47 | Neutral | 0.871 | Possibly Damaging | 0.298 | Benign | 4.20 | Benign | 0.40 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1231A>C | I411L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas a majority (premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Tools with uncertain or mixed outputs are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, yielding no definitive call; and Foldetta also reports an uncertain stability change. Overall, the majority of standard predictors lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence, though high‑accuracy tools remain inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -10.723 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 0.285 | Likely Benign | 0.0876 | 0.3539 | 1.02 | Ambiguous | 0.3 | 1.89 | Ambiguous | 1.46 | Ambiguous | 1.17 | Destabilizing | -1.84 | Neutral | 0.908 | Possibly Damaging | 0.943 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1231A>G | I411V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411V is reported in ClinVar as benign (ClinVar ID 1654508.0) and is not found in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Two tools predict a pathogenic outcome: PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are AlphaMissense‑Default, FoldX, Rosetta, premPS, and Foldetta. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) is uncertain. Overall, the preponderance of evidence points to a benign effect for I411V, which is consistent with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | Likely Benign | 1 | -6.290 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.212 | Likely Benign | 0.1112 | 0.3526 | 0.74 | Ambiguous | 0.0 | 0.82 | Ambiguous | 0.78 | Ambiguous | 0.99 | Ambiguous | -0.86 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.90 | Benign | 0.27 | Tolerated | 3.38 | 28 | 4 | 3 | -0.3 | -14.03 | 233.3 | 28.2 | -0.2 | 0.0 | -0.2 | 0.0 | X | Potentially Benign | The sec-butyl side chain of Ile411, located in the hydrophobic space between an anti-parallel β sheet strand (res. Pro398-Ile411) and an α helix (res. Asp684-Gln702), packs against multiple residues (e.g., Met409, Arg259). In the variant simulations, the side chain of Val411 is able to favorably fill the same hydrophobic niche despite its slightly smaller size. In short, the residue swap has no apparent negative effect on the structure based on the simulations. | ||||||||||||
| c.1231A>T | I411F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411F is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -13.377 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.503 | Likely Pathogenic | 0.0538 | 0.2853 | 5.71 | Destabilizing | 0.1 | 4.53 | Destabilizing | 5.12 | Destabilizing | 0.73 | Ambiguous | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.30 | Benign | 0.00 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.1232T>A | I411N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -14.426 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.556 | Likely Pathogenic | 0.0738 | 0.0700 | 3.00 | Destabilizing | 0.1 | 3.71 | Destabilizing | 3.36 | Destabilizing | 2.16 | Destabilizing | -6.42 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.1232T>C | I411T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I411T missense variant is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta’s assessment is uncertain. High‑accuracy methods give consistent pathogenic predictions: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -11.258 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.579 | Likely Pathogenic | 0.0903 | 0.1389 | 2.86 | Destabilizing | 0.0 | 1.75 | Ambiguous | 2.31 | Destabilizing | 1.86 | Destabilizing | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.31 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.1232T>G | I411S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -13.763 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.603 | Likely Pathogenic | 0.2262 | 0.1487 | 3.59 | Destabilizing | 0.2 | 3.83 | Destabilizing | 3.71 | Destabilizing | 1.91 | Destabilizing | -5.50 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.30 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.1233C>G | I411M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411M is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are supported by SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and AlphaMissense‑Optimized yield uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta also predicts pathogenicity. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -10.969 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.344 | Likely Benign | 0.0677 | 0.2848 | 1.30 | Ambiguous | 0.2 | 2.76 | Destabilizing | 2.03 | Destabilizing | 1.21 | Destabilizing | -2.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.31 | Benign | 0.00 | Affected | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||
| c.1234T>A | L412M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412M has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Five tools give uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized). High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie; and Foldetta is uncertain. Consequently, the overall evidence leans toward a pathogenic effect, with no ClinVar record to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -9.342 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 0.246 | Likely Benign | 0.0746 | 0.3482 | 0.75 | Ambiguous | 0.0 | 1.99 | Ambiguous | 1.37 | Ambiguous | 0.86 | Ambiguous | -1.84 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.05 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.1234T>G | L412V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -11.726 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.231 | Likely Benign | 0.1275 | 0.3378 | 3.65 | Destabilizing | 0.0 | 3.52 | Destabilizing | 3.59 | Destabilizing | 1.54 | Destabilizing | -2.76 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.25 | Benign | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1235T>C | L412S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized indicates pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also predicts pathogenic. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -13.884 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.557 | Likely Pathogenic | 0.2821 | 0.0505 | 4.03 | Destabilizing | 0.2 | 4.20 | Destabilizing | 4.12 | Destabilizing | 2.01 | Destabilizing | -5.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.22 | Benign | 0.00 | Affected | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||
| c.1235T>G | L412W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -13.436 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.503 | Likely Pathogenic | 0.0586 | 0.2664 | 8.44 | Destabilizing | 0.4 | 9.91 | Destabilizing | 9.18 | Destabilizing | 1.65 | Destabilizing | -5.53 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||
| c.1236G>C | L412F 2D  AIThe SynGAP1 missense variant L412F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Taken together, the consensus of the majority of evidence points to a pathogenic effect for L412F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -8.710 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.286 | Likely Benign | 0.0602 | 0.2891 | 7.00 | Destabilizing | 3.5 | 3.61 | Destabilizing | 5.31 | Destabilizing | 0.48 | Likely Benign | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.27 | Benign | 0.04 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1236G>T | L412F 2D AIThe SynGAP1 missense variant L412F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Taken together, the consensus of the majority of evidence points to a pathogenic effect for L412F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -8.710 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.283 | Likely Benign | 0.0602 | 0.2891 | 7.00 | Destabilizing | 3.5 | 3.61 | Destabilizing | 5.31 | Destabilizing | 0.48 | Likely Benign | -3.69 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.27 | Benign | 0.04 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1237C>A | P413T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P413T missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.851 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.554 | Likely Pathogenic | 0.1663 | 0.4670 | 3.22 | Destabilizing | 0.2 | 1.87 | Ambiguous | 2.55 | Destabilizing | 0.93 | Ambiguous | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.18 | Benign | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||
| c.1237C>G | P413A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P413A is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of algorithms—FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for P413A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.686 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.392 | Likely Benign | 0.3350 | 0.3863 | 2.38 | Destabilizing | 0.0 | 0.79 | Ambiguous | 1.59 | Ambiguous | 0.81 | Ambiguous | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.19 | Benign | 0.02 | Affected | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.1237C>T | P413S 2D 3DClick to see structure in 3D Viewer AISynGAP1 P413S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—indicate a pathogenic effect. High‑accuracy methods give a consistent pathogenic verdict: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) predicts pathogenic; FoldX alone supports pathogenicity while Rosetta remains uncertain. Taken together, the overwhelming majority of predictions support a pathogenic classification, and this is not contradicted by the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.586 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.509 | Likely Pathogenic | 0.3454 | 0.3819 | 3.06 | Destabilizing | 0.1 | 1.72 | Ambiguous | 2.39 | Destabilizing | 0.93 | Ambiguous | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.04 | Affected | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.1238C>A | P413H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P413H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; Rosetta is uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -13.376 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.546 | Likely Pathogenic | 0.1745 | 0.3480 | 4.89 | Destabilizing | 1.0 | 1.85 | Ambiguous | 3.37 | Destabilizing | 1.07 | Destabilizing | -8.29 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||
| c.1238C>G | P413R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P413R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The remaining methods, Foldetta and Rosetta, yield uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -15.523 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.562 | Likely Pathogenic | 0.1550 | 0.2199 | 2.40 | Destabilizing | 0.2 | 1.34 | Ambiguous | 1.87 | Ambiguous | 1.07 | Destabilizing | -8.29 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.1238C>T | P413L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P413L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.735 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.461 | Likely Benign | 0.2056 | 0.5614 | 2.61 | Destabilizing | 0.4 | 1.34 | Ambiguous | 1.98 | Ambiguous | 0.30 | Likely Benign | -9.21 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.1240A>C | M414L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. Uncertain predictions come from premPS and ESM1b. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the preponderance of evidence indicates that M414L is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -7.980 | In-Between | 0.779 | Likely Pathogenic | Likely Benign | 0.336 | Likely Benign | 0.1323 | 0.4236 | 0.26 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.30 | Likely Benign | 0.64 | Ambiguous | -2.40 | Neutral | 0.559 | Possibly Damaging | 0.495 | Possibly Damaging | 3.63 | Benign | 0.90 | Tolerated | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||
| c.1240A>G | M414V 2D AISynGAP1 M414V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; the remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are inconclusive. The SGM consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic majority. High‑accuracy assessments give AlphaMissense‑Optimized benign, SGM consensus pathogenic, and Foldetta uncertain. Because the high‑accuracy predictions are divided and the overall tool set is evenly split, there is no definitive evidence for pathogenicity or benignity. Thus, the variant is most likely inconclusive, and this lack of consensus does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | Uncertain | 1 | -8.003 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 0.261 | Likely Benign | 0.2585 | 0.3482 | 1.81 | Ambiguous | 0.4 | 1.73 | Ambiguous | 1.77 | Ambiguous | 0.95 | Ambiguous | -2.95 | Deleterious | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.43 | Benign | 0.24 | Tolerated | 2 | 1 | 2.3 | -32.06 | ||||||||||||||||||||||||
| c.1240A>T | M414L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. Uncertain predictions come from premPS and ESM1b. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the preponderance of evidence indicates that M414L is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -7.980 | In-Between | 0.779 | Likely Pathogenic | Likely Benign | 0.336 | Likely Benign | 0.1323 | 0.4236 | 0.26 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.30 | Likely Benign | 0.64 | Ambiguous | -2.40 | Neutral | 0.559 | Possibly Damaging | 0.495 | Possibly Damaging | 3.63 | Benign | 0.90 | Tolerated | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||
| c.1241T>A | M414K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. FoldX and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is unavailable. Based on the overwhelming agreement among the majority of prediction tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -13.537 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.503 | Likely Pathogenic | 0.1299 | 0.0888 | 1.18 | Ambiguous | 0.1 | 2.39 | Destabilizing | 1.79 | Ambiguous | 1.50 | Destabilizing | -5.03 | Deleterious | 0.942 | Possibly Damaging | 0.860 | Possibly Damaging | 3.40 | Benign | 0.04 | Affected | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||
| c.1241T>C | M414T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M414T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta; Rosetta remains uncertain. High‑accuracy methods all support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta predicts a destabilizing, pathogenic outcome. Consequently, the consensus of the most reliable predictors classifies M414T as pathogenic, with no conflict with the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -8.698 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.406 | Likely Benign | 0.1771 | 0.1976 | 2.04 | Destabilizing | 0.1 | 1.96 | Ambiguous | 2.00 | Destabilizing | 1.27 | Destabilizing | -5.00 | Deleterious | 0.997 | Probably Damaging | 0.972 | Probably Damaging | 3.41 | Benign | 0.08 | Tolerated | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||
| c.1241T>G | M414R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence indicates that M414R is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -13.404 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.525 | Likely Pathogenic | 0.1509 | 0.1037 | 1.17 | Ambiguous | 0.1 | 2.58 | Destabilizing | 1.88 | Ambiguous | 1.45 | Destabilizing | -5.20 | Deleterious | 0.972 | Probably Damaging | 0.895 | Possibly Damaging | 3.38 | Benign | 0.03 | Affected | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||
| c.1242G>A | M414I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 M414I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, more tools (five) predict pathogenicity than benign (four), and no ClinVar evidence contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.265 | Likely Benign | 0.1168 | 0.3161 | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1242G>C | M414I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta is uncertain, so these results are treated as unavailable. Overall, the majority of evaluated tools (5 pathogenic vs 4 benign) and the single high‑accuracy pathogenic prediction support a likely pathogenic classification. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.265 | Likely Benign | 0.1168 | 0.3161 | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1242G>T | M414I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2), and Foldetta is uncertain, so these results are treated as unavailable. Overall, the majority of evaluated tools (5 pathogenic vs 4 benign) and the single high‑accuracy pathogenic prediction support a likely pathogenic classification. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -6.203 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.265 | Likely Benign | 0.1168 | 0.3161 | 0.83 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.85 | Ambiguous | 0.84 | Ambiguous | -3.00 | Deleterious | 0.870 | Possibly Damaging | 0.801 | Possibly Damaging | 3.44 | Benign | 0.36 | Tolerated | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1243G>A | E415K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E415K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus shows AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall balance of predictions—particularly the two high‑accuracy pathogenic calls versus one benign—the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.433 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.326 | Likely Benign | 0.2174 | 0.3860 | -0.07 | Likely Benign | 0.3 | -0.13 | Likely Benign | -0.10 | Likely Benign | 0.46 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.22 | Benign | 0.03 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1243G>C | E415Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E415Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, seven tools predict pathogenicity versus six predicting benignity, and the two most reliable predictors (AlphaMissense‑Optimized and SGM‑Consensus) both favor pathogenicity. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -9.085 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.236 | Likely Benign | 0.1084 | 0.3474 | 0.29 | Likely Benign | 0.2 | 0.22 | Likely Benign | 0.26 | Likely Benign | 0.01 | Likely Benign | -2.63 | Deleterious | 0.997 | Probably Damaging | 0.973 | Probably Damaging | 3.26 | Benign | 0.08 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1244A>C | E415A 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant E415A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are given by FoldX and premPS. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy predictions support this view. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.743 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.435 | Likely Benign | 0.2909 | 0.3432 | 0.61 | Ambiguous | 0.2 | 0.05 | Likely Benign | 0.33 | Likely Benign | 0.53 | Ambiguous | -5.56 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.19 | Benign | 0.03 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1244A>G | E415G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E415G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for E415G. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -12.244 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.432 | Likely Benign | 0.2518 | 0.3158 | 1.16 | Ambiguous | 0.2 | 0.88 | Ambiguous | 1.02 | Ambiguous | 0.65 | Ambiguous | -6.45 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.20 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1244A>T | E415V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E415V missense variant is not reported in ClinVar or gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts benign. No evidence is missing or inconclusive. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.182 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.441 | Likely Benign | 0.0650 | 0.4218 | 0.56 | Ambiguous | 0.2 | 0.14 | Likely Benign | 0.35 | Likely Benign | 0.40 | Likely Benign | -6.52 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.13 | Benign | 0.02 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1245G>C | E415D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E415D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while Foldetta predicts a benign effect. Overall, the balance of evidence leans toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -7.766 | In-Between | 0.952 | Likely Pathogenic | Ambiguous | 0.220 | Likely Benign | 0.1777 | 0.2075 | 0.75 | Ambiguous | 0.1 | 0.21 | Likely Benign | 0.48 | Likely Benign | 0.49 | Likely Benign | -2.60 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.22 | Benign | 0.04 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1245G>T | E415D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta indicates a benign effect. Overall, the majority of standard tools lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -7.766 | In-Between | 0.952 | Likely Pathogenic | Ambiguous | 0.220 | Likely Benign | 0.1777 | 0.2075 | 0.75 | Ambiguous | 0.1 | 0.21 | Likely Benign | 0.48 | Likely Benign | 0.49 | Likely Benign | -2.60 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.22 | Benign | 0.04 | Affected | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1246C>A | L416I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 L416I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that remain inconclusive are FoldX, Rosetta, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion is not contradicted by any ClinVar annotation, as the variant has no existing ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -8.613 | Likely Pathogenic | 0.396 | Ambiguous | Likely Benign | 0.127 | Likely Benign | 0.1073 | 0.3480 | 0.57 | Ambiguous | 0.0 | 0.69 | Ambiguous | 0.63 | Ambiguous | 0.50 | Likely Benign | -1.28 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.38 | Benign | 0.37 | Tolerated | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1246C>G | L416V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L416V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for the variant. This conclusion is not contradicted by any ClinVar annotation, as the variant is not present in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -7.861 | In-Between | 0.310 | Likely Benign | Likely Benign | 0.124 | Likely Benign | 0.1563 | 0.3550 | 1.46 | Ambiguous | 0.0 | 1.78 | Ambiguous | 1.62 | Ambiguous | 0.45 | Likely Benign | -1.47 | Neutral | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.42 | Benign | 0.53 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1247T>A | L416Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L416Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict benign. Only two tools, polyPhen‑2 (HumDiv and HumVar), predict a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta remains uncertain. Overall, the evidence strongly supports a benign classification for this variant, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -6.445 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.187 | Likely Benign | 0.1281 | 0.0860 | 1.17 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.86 | Ambiguous | 0.88 | Ambiguous | -1.07 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.46 | Tolerated | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1247T>C | L416P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L416P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and the SGM Consensus). High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, which is consistent with the lack of ClinVar reporting and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -8.859 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.284 | Likely Benign | 0.3589 | 0.1353 | 2.59 | Destabilizing | 0.1 | 6.23 | Destabilizing | 4.41 | Destabilizing | 1.27 | Destabilizing | -3.56 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.35 | Benign | 0.21 | Tolerated | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1247T>G | L416R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L416R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans toward benign, while Foldetta remains uncertain. Overall, the majority of reliable predictors classify the variant as benign, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -8.600 | Likely Pathogenic | 0.511 | Ambiguous | Likely Benign | 0.238 | Likely Benign | 0.1445 | 0.0702 | 0.71 | Ambiguous | 0.0 | 0.97 | Ambiguous | 0.84 | Ambiguous | 0.84 | Ambiguous | -2.05 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.35 | Benign | 0.43 | Tolerated | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||
| c.1249T>A | Y417N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -13.912 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.561 | Likely Pathogenic | 0.2482 | 0.0728 | 3.94 | Destabilizing | 0.2 | 3.69 | Destabilizing | 3.82 | Destabilizing | 2.60 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.97 | Benign | 0.00 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.1249T>C | Y417H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417H is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for Y417H. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -11.447 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.513 | Likely Pathogenic | 0.2596 | 0.0668 | 3.22 | Destabilizing | 0.1 | 2.80 | Destabilizing | 3.01 | Destabilizing | 1.54 | Destabilizing | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.97 | Benign | 0.00 | Affected | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.1249T>G | Y417D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -14.955 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.688 | Likely Pathogenic | 0.4388 | 0.0400 | 5.13 | Destabilizing | 0.1 | 5.37 | Destabilizing | 5.25 | Destabilizing | 2.43 | Destabilizing | -9.55 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.96 | Benign | 0.00 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.1250A>C | Y417S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, while all other evaluated algorithms—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -14.339 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.593 | Likely Pathogenic | 0.4408 | 0.1961 | 4.36 | Destabilizing | 0.1 | 5.32 | Destabilizing | 4.84 | Destabilizing | 2.17 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.00 | Affected | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.1250A>G | Y417C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y417C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -12.021 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.597 | Likely Pathogenic | 0.2960 | 0.2005 | 4.03 | Destabilizing | 0.1 | 3.81 | Destabilizing | 3.92 | Destabilizing | 2.52 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.95 | Benign | 0.00 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.1250A>T | Y417F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y417F variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized and premPS. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta) as Benign, and AlphaMissense‑Optimized as Uncertain. Overall, the majority of tools and the SGM‑Consensus score suggest a pathogenic effect, while Foldetta indicates a benign effect; the variant’s status is not contradicted by ClinVar (no entry). Thus, based on the available predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.346865 | Uncertain | 0.958 | 0.250 | 0.000 | -11.368 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 0.367 | Likely Benign | 0.2617 | 0.3098 | 0.47 | Likely Benign | 0.1 | -0.09 | Likely Benign | 0.19 | Likely Benign | 0.97 | Ambiguous | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.03 | Benign | 0.06 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||
| c.1252A>C | K418Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K418Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -11.404 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.263 | Likely Benign | 0.4105 | 0.0696 | 0.10 | Likely Benign | 0.1 | 0.17 | Likely Benign | 0.14 | Likely Benign | 0.30 | Likely Benign | -3.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.55 | Benign | 0.13 | Tolerated | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.1252A>G | K418E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418E is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evaluated tools (seven pathogenic vs four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for K418E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -12.443 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.367 | Likely Benign | 0.3578 | 0.0471 | 0.63 | Ambiguous | 0.0 | 0.80 | Ambiguous | 0.72 | Ambiguous | 0.47 | Likely Benign | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.53 | Benign | 0.07 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1253A>C | K418T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K418T variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of tools (10 pathogenic vs. 5 benign) support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -11.994 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.392 | Likely Benign | 0.1975 | 0.1894 | 0.39 | Likely Benign | 0.1 | 0.55 | Ambiguous | 0.47 | Likely Benign | 0.41 | Likely Benign | -5.36 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.37 | Benign | 0.04 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1253A>G | K418R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, ESM1b, FATHMM, PROVEAN, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus methods give a benign verdict: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. premPS is uncertain and therefore not considered evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -6.809 | Likely Benign | 0.635 | Likely Pathogenic | Likely Benign | 0.229 | Likely Benign | 0.4384 | 0.1151 | -0.18 | Likely Benign | 0.1 | 0.12 | Likely Benign | -0.03 | Likely Benign | 0.56 | Ambiguous | -2.46 | Neutral | 0.994 | Probably Damaging | 0.962 | Probably Damaging | 3.37 | Benign | 0.04 | Affected | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.1253A>T | K418I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. In contrast, the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K418I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -14.895 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.428 | Likely Benign | 0.1297 | 0.2432 | 0.51 | Ambiguous | 0.0 | 0.64 | Ambiguous | 0.58 | Ambiguous | 0.27 | Likely Benign | -7.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.1254A>C | K418N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM. The majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence indicates that K418N is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -13.310 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | 0.3483 | 0.0606 | 0.57 | Ambiguous | 0.0 | 0.77 | Ambiguous | 0.67 | Ambiguous | 0.56 | Ambiguous | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1254A>T | K418N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions are provided by REVEL and FATHMM, whereas pathogenic predictions are given by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta’s stability analysis is inconclusive. Overall, the majority of reliable predictors classify K418N as pathogenic, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -13.310 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | 0.3483 | 0.0606 | 0.57 | Ambiguous | 0.0 | 0.77 | Ambiguous | 0.67 | Ambiguous | 0.56 | Ambiguous | -4.41 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.04 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1255G>A | E419K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419K missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Foldetta and Rosetta give uncertain results and are not counted in either group. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus predicts likely pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact for E419K. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -12.257 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.399 | Likely Benign | 0.2759 | 0.6899 | 0.01 | Likely Benign | 0.1 | 1.30 | Ambiguous | 0.66 | Ambiguous | -0.03 | Likely Benign | -3.75 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.36 | Benign | 0.07 | Tolerated | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1255G>C | E419Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the predictions are split, with a slight majority leaning toward pathogenicity. The variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -9.268 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 0.280 | Likely Benign | 0.1499 | 0.6938 | 0.01 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.19 | Likely Benign | 0.02 | Likely Benign | -2.80 | Deleterious | 0.997 | Probably Damaging | 0.973 | Probably Damaging | 3.41 | Benign | 0.04 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1256A>C | E419A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -10.951 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 0.398 | Likely Benign | 0.4051 | 0.6705 | 0.56 | Ambiguous | 0.1 | 0.94 | Ambiguous | 0.75 | Ambiguous | 0.28 | Likely Benign | -5.60 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1256A>G | E419G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E419G is listed in ClinVar with an uncertain significance (ClinVar ID 2004834.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms likely pathogenic, and the Foldetta stability analysis is inconclusive. No evidence from FoldX, Rosetta, or premPS is available. Overall, the preponderance of predictions indicates that E419G is most likely pathogenic, which contrasts with the current ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | Uncertain | 1 | -10.589 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.469 | Likely Benign | 0.2992 | 0.5728 | 1.41 | Ambiguous | 0.0 | 1.94 | Ambiguous | 1.68 | Ambiguous | 0.83 | Ambiguous | -6.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.31 | Benign | 0.02 | Affected | 3.37 | 29 | 0 | -2 | 3.1 | -72.06 | 165.3 | 110.8 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Pathogenic | The carboxylate group of Glu419, located on an α helix (res. Met414-Glu436), forms a salt bridge with the side chain of either Arg716 or Lys418 from an opposing helix (res. Pro713-Arg726). The backbone amide group of Glu419 does not form H-bonds, resulting in a slight bend in the α helix. Thus, although glycine is known as an “α helix breaker,” the residue swap does not disrupt the continuity or integrity of the α helix. However, because Gly419 cannot form a salt bridge with the guanidinium group of the Arg716 side chain, the C2-GAP domain tertiary structure could be compromised during folding. | ||||||||||||
| c.1256A>T | E419V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, FATHMM, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from the high‑accuracy tools contradicts the pathogenic prediction. Overall, the majority of computational evidence points to a pathogenic effect, which is consistent with the lack of ClinVar reporting and gnomAD absence, suggesting the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -12.290 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.494 | Likely Benign | 0.0953 | 0.6834 | 0.45 | Likely Benign | 0.0 | 1.41 | Ambiguous | 0.93 | Ambiguous | 0.27 | Likely Benign | -6.55 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1257G>C | E419D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or inconclusive predictions come from Foldetta, AlphaMissense‑Optimized, ESM1b, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains uncertain (unavailable). Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -7.036 | In-Between | 0.869 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | 0.1966 | 0.4906 | 0.17 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.52 | Ambiguous | 0.48 | Likely Benign | -2.40 | Neutral | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.33 | Benign | 0.10 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1257G>T | E419D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or inconclusive predictions come from Foldetta, AlphaMissense‑Optimized, ESM1b, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains uncertain (unavailable). Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -7.036 | In-Between | 0.869 | Likely Pathogenic | Ambiguous | 0.170 | Likely Benign | 0.1966 | 0.4906 | 0.17 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.52 | Ambiguous | 0.48 | Likely Benign | -2.40 | Neutral | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.33 | Benign | 0.10 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1258T>A | F420I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -12.567 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.330 | Likely Benign | 0.1864 | 0.2113 | 2.88 | Destabilizing | 0.0 | 3.64 | Destabilizing | 3.26 | Destabilizing | 1.25 | Destabilizing | -5.46 | Deleterious | 0.575 | Possibly Damaging | 0.059 | Benign | 3.22 | Benign | 0.02 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.1258T>C | F420L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect comprise the SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated predictors (six pathogenic vs. five benign) indicate that F420L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -8.432 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.262 | Likely Benign | 0.2053 | 0.3016 | 1.76 | Ambiguous | 0.0 | 1.41 | Ambiguous | 1.59 | Ambiguous | 1.04 | Destabilizing | -5.39 | Deleterious | 0.009 | Benign | 0.005 | Benign | 4.22 | Benign | 0.39 | Tolerated | 3.37 | 29 | 2 | 0 | 1.0 | -34.02 | 231.1 | 13.2 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Benign | In the WT, the phenyl ring of the Phe420 side chain, located on an α helix (res. Met414-Glu436), packs against hydrophobic residues in the interhelix area of the GAP domain (e.g., Leu689, Leu714, Leu717, Leu718). In the variant simulations, the iso-butyl side chain of Leu420 also packs into the hydrophobic inter-helix niche, but due to its smaller size, the resulting steric interactions are not as favorable as with phenylalanine. In short, the residue swap does not cause severe effects on the protein structure based on the variant simulations. | ||||||||||||||
| c.1258T>G | F420V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts Pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy tool consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -11.849 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.402 | Likely Benign | 0.2038 | 0.2022 | 3.42 | Destabilizing | 0.1 | 3.35 | Destabilizing | 3.39 | Destabilizing | 1.58 | Destabilizing | -6.41 | Deleterious | 0.495 | Possibly Damaging | 0.191 | Benign | 3.16 | Benign | 0.01 | Affected | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.1259T>A | F420Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show mixed results. Benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are reported by premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments indicate that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -12.138 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | 0.1609 | 0.1498 | 1.18 | Ambiguous | 0.1 | 0.96 | Ambiguous | 1.07 | Ambiguous | 1.31 | Destabilizing | -2.80 | Deleterious | 0.306 | Benign | 0.100 | Benign | 3.09 | Benign | 0.03 | Affected | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.1259T>C | F420S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420S (ClinVar ID 981441.0) is reported as Pathogenic in ClinVar and is not present in gnomAD. Prediction tools largely agree on a deleterious effect: all listed predictors except FATHMM return a pathogenic or likely pathogenic call. The single benign prediction comes from FATHMM. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts Pathogenic. No predictions or folding‑stability results are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | Likely Pathogenic | 1 | -13.231 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.544 | Likely Pathogenic | 0.4167 | 0.0200 | 5.34 | Destabilizing | 0.1 | 5.73 | Destabilizing | 5.54 | Destabilizing | 2.14 | Destabilizing | -7.43 | Deleterious | 0.998 | Probably Damaging | 0.938 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 29 | -3 | -2 | -3.6 | -60.10 | 213.3 | 57.8 | 0.0 | 0.0 | -0.4 | 0.1 | X | Potentially Pathogenic | In the WT, the phenyl ring of the Phe420 side chain, located on an α helix (res. Met414-Glu436), packs against hydrophobic residues in the interhelix area of the GAP domain (e.g., Leu689, Leu714, Leu717, Leu718). Although no large-scale adverse effects are seen in the variant simulations, the polar hydroxyl group of Ser420 is not suitable for the hydrophobic inter-helix space. Thus, the residue swap could affect protein folding. In theory, the introduced hydroxyl group could also lower the α helix integrity by H-bonding with the backbone atoms of neighboring residues in the same α helix. However, no such effect is seen in the variant simulations. | ||||||||||||
| c.1259T>G | F420C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. When grouped by consensus, the benign prediction is singular (FATHMM), whereas the pathogenic predictions comprise the remaining eleven tools. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -11.931 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.500 | Likely Pathogenic | 0.2458 | 0.0662 | 4.31 | Destabilizing | 0.1 | 5.11 | Destabilizing | 4.71 | Destabilizing | 2.49 | Destabilizing | -7.40 | Deleterious | 0.998 | Probably Damaging | 0.869 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.1260T>A | F420L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect comprise the SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated predictors (six pathogenic vs. five benign) indicate that F420L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -8.432 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | 0.2053 | 0.3016 | 1.76 | Ambiguous | 0.0 | 1.41 | Ambiguous | 1.59 | Ambiguous | 1.04 | Destabilizing | -5.39 | Deleterious | 0.009 | Benign | 0.005 | Benign | 4.22 | Benign | 0.39 | Tolerated | 3.37 | 29 | 2 | 0 | 1.0 | -34.02 | 231.1 | 13.2 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Benign | In the WT, the phenyl ring of the Phe420 side chain, located on an α helix (res. Met414-Glu436), packs against hydrophobic residues in the interhelix area of the GAP domain (e.g., Leu689, Leu714, Leu717, Leu718). In the variant simulations, the iso-butyl side chain of Leu420 also packs into the hydrophobic inter-helix niche, but due to its smaller size, the resulting steric interactions are not as favorable as with phenylalanine. In short, the residue swap does not cause severe effects on the protein structure based on the variant simulations. | ||||||||||||||
| c.1260T>G | F420L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420L is listed in ClinVar (ID 1397885.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Those that predict a pathogenic effect comprise premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, Foldetta) yield inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus also as pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic impact, which does not contradict the ClinVar “Uncertain” status but suggests the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | Uncertain | 1 | -8.432 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.146 | Likely Benign | 0.2053 | 0.3016 | 1.76 | Ambiguous | 0.0 | 1.41 | Ambiguous | 1.59 | Ambiguous | 1.04 | Destabilizing | -5.39 | Deleterious | 0.009 | Benign | 0.005 | Benign | 4.22 | Benign | 0.39 | Tolerated | 3.37 | 29 | 2 | 0 | 1.0 | -34.02 | 231.1 | 13.2 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Benign | In the WT, the phenyl ring of the Phe420 side chain, located on an α helix (res. Met414-Glu436), packs against hydrophobic residues in the interhelix area of the GAP domain (e.g., Leu689, Leu714, Leu717, Leu718). In the variant simulations, the iso-butyl side chain of Leu420 also packs into the hydrophobic inter-helix niche, but due to its smaller size, the resulting steric interactions are not as favorable as with phenylalanine. In short, the residue swap does not cause severe effects on the protein structure based on the variant simulations. | ||||||||||||
| c.1261G>A | A421T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A421T is not reported in ClinVar and is present in gnomAD (ID 6‑33438166‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of consensus predictions lean toward a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | 6-33438166-G-A | 1 | 6.19e-7 | -9.217 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.179 | Likely Benign | 0.1346 | 0.4439 | 0.75 | Ambiguous | 0.2 | 0.18 | Likely Benign | 0.47 | Likely Benign | 0.99 | Ambiguous | -3.12 | Deleterious | 0.353 | Benign | 0.136 | Benign | 3.43 | Benign | 0.09 | Tolerated | 3.37 | 29 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||
| c.1261G>C | A421P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A421P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL, FATHMM, and polyPhen‑2 HumVar, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a pathogenic effect. Taken together, the overwhelming majority of evidence points to a pathogenic impact for A421P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -13.126 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.371 | Likely Benign | 0.1963 | 0.3343 | 4.51 | Destabilizing | 0.2 | 8.77 | Destabilizing | 6.64 | Destabilizing | 1.17 | Destabilizing | -4.31 | Deleterious | 0.855 | Possibly Damaging | 0.420 | Benign | 3.39 | Benign | 0.04 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1261G>T | A421S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A421S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from PROVEAN, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Pathogenic. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus predicts pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Stability calculations from FoldX and Rosetta are uncertain, and premPS is unavailable. Overall, the majority of tools lean toward a pathogenic interpretation, and this aligns with the SGM‑Consensus result; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -9.220 | Likely Pathogenic | 0.715 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | 0.2247 | 0.3621 | 0.66 | Ambiguous | 0.1 | 1.12 | Ambiguous | 0.89 | Ambiguous | 0.70 | Ambiguous | -2.50 | Deleterious | 0.058 | Benign | 0.072 | Benign | 3.46 | Benign | 0.08 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1262C>A | A421E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A421E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas pathogenic calls are made by ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, Rosetta, premPS, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods give mixed results: FoldX is uncertain, Foldetta is uncertain, and Rosetta alone predicts pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence, including the high‑accuracy tools, points to a pathogenic impact for A421E, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -11.993 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.233 | Likely Benign | 0.1288 | 0.1830 | 0.63 | Ambiguous | 0.2 | 2.07 | Destabilizing | 1.35 | Ambiguous | 1.30 | Destabilizing | -4.24 | Deleterious | 0.368 | Benign | 0.144 | Benign | 3.44 | Benign | 0.14 | Tolerated | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||
| c.1262C>G | A421G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A421G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of tools and the SGM Consensus favor a pathogenic interpretation, while a minority suggest benign. Because there is no ClinVar entry, the predictions do not contradict existing clinical classification. The variant is most likely pathogenic based on the collective computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -9.699 | Likely Pathogenic | 0.757 | Likely Pathogenic | Likely Benign | 0.137 | Likely Benign | 0.1692 | 0.2499 | 1.47 | Ambiguous | 0.1 | 2.13 | Destabilizing | 1.80 | Ambiguous | 1.19 | Destabilizing | -3.59 | Deleterious | 0.536 | Possibly Damaging | 0.176 | Benign | 3.41 | Benign | 0.05 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1262C>T | A421V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A421V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) also predicts pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, predicts benign. Rosetta alone is uncertain and is treated as unavailable. Overall, the majority of high‑confidence tools favor a pathogenic effect, so A421V is most likely pathogenic, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.404927 | Uncertain | 0.965 | 0.257 | 0.000 | -8.167 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.111 | Likely Benign | 0.1055 | 0.3738 | -0.05 | Likely Benign | 0.1 | -0.82 | Ambiguous | -0.44 | Likely Benign | -0.06 | Likely Benign | -3.15 | Deleterious | 0.538 | Possibly Damaging | 0.113 | Benign | 3.50 | Benign | 0.14 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1264G>A | E422K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E422K missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus also indicates Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -13.042 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.346 | Likely Benign | 0.1995 | 0.5129 | 0.30 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.20 | Likely Benign | 0.32 | Likely Benign | -3.52 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.39 | Benign | 0.04 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1264G>C | E422Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E422Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and FATHMM, while those that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -9.460 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.208 | Likely Benign | 0.1045 | 0.4913 | 0.32 | Likely Benign | 0.0 | 0.21 | Likely Benign | 0.27 | Likely Benign | -0.15 | Likely Benign | -2.26 | Neutral | 0.997 | Probably Damaging | 0.973 | Probably Damaging | 3.38 | Benign | 0.03 | Affected | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.1265A>C | E422A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E422A missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates likely pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the balance of evidence (seven pathogenic versus six benign predictions) points to a likely pathogenic effect for E422A, and this conclusion is not contradicted by the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -12.088 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.371 | Likely Benign | 0.2949 | 0.4459 | 0.49 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.37 | Likely Benign | 0.26 | Likely Benign | -5.43 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1265A>G | E422G 2D 3DClick to see structure in 3D Viewer AISynGAP1 E422G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, premPS, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are provided by FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy analyses indicate that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts a likely pathogenic effect, whereas AlphaMissense‑Optimized remains inconclusive and Foldetta shows no definitive stability change. Overall, the majority of evidence points toward a pathogenic impact for E422G, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -11.468 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.488 | Likely Benign | 0.2440 | 0.4184 | 1.13 | Ambiguous | 0.0 | 1.25 | Ambiguous | 1.19 | Ambiguous | 0.39 | Likely Benign | -6.38 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1265A>T | E422V 2D 3DClick to see structure in 3D Viewer AISynGAP1 E422V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. FoldX remains uncertain. Overall, the majority of high‑confidence tools lean toward pathogenicity, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -12.371 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.489 | Likely Benign | 0.0609 | 0.5457 | 0.90 | Ambiguous | 0.1 | -0.02 | Likely Benign | 0.44 | Likely Benign | 0.24 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1266G>C | E422D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E422D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b is uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of tools (six benign vs five pathogenic) lean toward a benign effect, but the two most accurate predictors and the consensus vote indicate a pathogenic tendency. Thus, the variant is most likely benign based on the broader tool set, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -7.092 | In-Between | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.199 | Likely Benign | 0.1686 | 0.2864 | 0.39 | Likely Benign | 0.0 | -0.03 | Likely Benign | 0.18 | Likely Benign | 0.21 | Likely Benign | -2.76 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.38 | Benign | 0.07 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1266G>T | E422D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E422D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b is uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of tools (six benign vs five pathogenic) lean toward a benign effect, but the two most accurate predictors and the consensus vote indicate a pathogenic tendency. Thus, the variant is most likely benign based on the broader tool set, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -7.092 | In-Between | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.199 | Likely Benign | 0.1686 | 0.2864 | 0.39 | Likely Benign | 0.0 | -0.03 | Likely Benign | 0.18 | Likely Benign | 0.21 | Likely Benign | -2.76 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.38 | Benign | 0.07 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1267T>A | Y423N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include SIFT and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -10.937 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.501 | Likely Pathogenic | 0.1405 | 0.0412 | 3.97 | Destabilizing | 0.1 | 4.08 | Destabilizing | 4.03 | Destabilizing | 2.07 | Destabilizing | -7.47 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.06 | Tolerated | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.1267T>C | Y423H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y423H missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default. AlphaMissense‑Optimized is reported as uncertain. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and therefore inconclusive, while Foldetta predicts a pathogenic impact. Overall, the majority of evaluated tools (10 pathogenic vs. 4 benign) support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -6.638 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.257 | Likely Benign | 0.1603 | 0.0352 | 3.09 | Destabilizing | 0.1 | 2.44 | Destabilizing | 2.77 | Destabilizing | 1.66 | Destabilizing | -3.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.61 | Tolerated | 0 | 2 | -1.9 | -26.03 | ||||||||||||||||||||||||||
| c.1267T>G | Y423D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -13.279 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.553 | Likely Pathogenic | 0.3262 | 0.0412 | 4.67 | Destabilizing | 0.1 | 4.79 | Destabilizing | 4.73 | Destabilizing | 1.78 | Destabilizing | -8.28 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.38 | Benign | 0.04 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.1268A>C | Y423S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the preponderance of evidence points to a pathogenic effect for Y423S. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -10.847 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.345 | Likely Benign | 0.3152 | 0.1259 | 4.28 | Destabilizing | 0.1 | 4.78 | Destabilizing | 4.53 | Destabilizing | 1.95 | Destabilizing | -7.39 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.09 | Tolerated | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.1268A>G | Y423C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (treated as unavailable), SGM‑Consensus as Likely Pathogenic, and Foldetta as Pathogenic. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -9.003 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.286 | Likely Benign | 0.2381 | 0.1096 | 4.01 | Destabilizing | 0.1 | 4.49 | Destabilizing | 4.25 | Destabilizing | 1.84 | Destabilizing | -7.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.03 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.1268A>T | Y423F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423F is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly classify the substitution as benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect, while premPS is inconclusive. High‑accuracy methods give consistent benign results: AlphaMissense‑Optimized is benign, the SGM‑Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Overall, the overwhelming majority of evidence supports a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -5.533 | Likely Benign | 0.181 | Likely Benign | Likely Benign | 0.149 | Likely Benign | 0.1934 | 0.2337 | 0.03 | Likely Benign | 0.1 | -0.05 | Likely Benign | -0.01 | Likely Benign | 0.76 | Ambiguous | -2.30 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.45 | Benign | 0.60 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||
| c.1270G>A | V424I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V424I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. The only inconclusive results come from FoldX (uncertain) and Foldetta (uncertain). When high‑accuracy methods are considered separately, AlphaMissense‑Optimized predicts benign, the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also predicts benign, while Foldetta remains uncertain. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -3.814 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.0874 | 0.2609 | -1.04 | Ambiguous | 0.1 | -0.48 | Likely Benign | -0.76 | Ambiguous | 0.02 | Likely Benign | -0.15 | Neutral | 0.013 | Benign | 0.006 | Benign | 3.50 | Benign | 0.63 | Tolerated | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||
| c.1270G>C | V424L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V424L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome, while SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely benign classification. Stability‑based methods are inconclusive: FoldX is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -4.941 | Likely Benign | 0.742 | Likely Pathogenic | Likely Benign | 0.159 | Likely Benign | 0.1018 | 0.2680 | -0.90 | Ambiguous | 0.2 | -0.41 | Likely Benign | -0.66 | Ambiguous | 0.43 | Likely Benign | -1.68 | Neutral | 0.327 | Benign | 0.026 | Benign | 4.50 | Benign | 0.59 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1270G>T | V424F 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant V424F is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) yield uncertain or unavailable results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -10.947 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.275 | Likely Benign | 0.0816 | 0.2094 | 1.99 | Ambiguous | 0.3 | -0.37 | Likely Benign | 0.81 | Ambiguous | 0.55 | Ambiguous | -3.66 | Deleterious | 0.995 | Probably Damaging | 0.775 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||
| c.1271T>A | V424D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V424D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -15.531 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.615 | Likely Pathogenic | 0.1536 | 0.0845 | 3.60 | Destabilizing | 0.1 | 3.50 | Destabilizing | 3.55 | Destabilizing | 2.13 | Destabilizing | -5.87 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| c.1271T>C | V424A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V424A is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as unavailable, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. Based on the collective evidence, the variant is most likely pathogenic; this conclusion is not contradicted by the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -9.665 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.245 | Likely Benign | 0.2105 | 0.1355 | 2.31 | Destabilizing | 0.1 | 2.54 | Destabilizing | 2.43 | Destabilizing | 2.10 | Destabilizing | -3.45 | Deleterious | 0.997 | Probably Damaging | 0.961 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| c.1271T>G | V424G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V424G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic consensus (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -13.697 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.622 | Likely Pathogenic | 0.1396 | 0.2029 | 3.90 | Destabilizing | 0.1 | 4.84 | Destabilizing | 4.37 | Destabilizing | 2.44 | Destabilizing | -6.26 | Deleterious | 0.994 | Probably Damaging | 1.000 | Probably Damaging | 3.34 | Benign | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1273A>C | T425P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as deleterious, while only FATHMM predicts a benign outcome; premPS is uncertain. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Taken together, the overwhelming majority of evidence supports a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -12.318 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.512 | Likely Pathogenic | 0.1815 | 0.3469 | 2.81 | Destabilizing | 0.3 | 6.49 | Destabilizing | 4.65 | Destabilizing | 0.77 | Ambiguous | -5.16 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.03 | Affected | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.1273A>G | T425A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Two tools (premPS and AlphaMissense‑Optimized) give uncertain results and are treated as unavailable. High‑accuracy assessments show SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign, and AlphaMissense‑Optimized as uncertain. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -8.945 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 0.372 | Likely Benign | 0.2971 | 0.2572 | -0.31 | Likely Benign | 0.1 | -0.05 | Likely Benign | -0.18 | Likely Benign | 0.70 | Ambiguous | -4.17 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.42 | Benign | 0.09 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.1273A>T | T425S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, Rosetta) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -7.420 | In-Between | 0.676 | Likely Pathogenic | Likely Benign | 0.275 | Likely Benign | 0.2511 | 0.2324 | 0.22 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.50 | Ambiguous | 0.63 | Ambiguous | -3.05 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||
| c.1274C>A | T425N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions labeled uncertain (Foldetta, premPS, AlphaMissense‑Optimized, Rosetta) are treated as unavailable. High‑accuracy assessments further indicate a likely pathogenic outcome from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and an uncertain result from AlphaMissense‑Optimized and Foldetta. Overall, the majority of definitive predictions support a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -10.709 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.185 | Likely Benign | 0.1169 | 0.2843 | 0.19 | Likely Benign | 0.1 | 0.81 | Ambiguous | 0.50 | Ambiguous | 0.82 | Ambiguous | -3.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.44 | Benign | 0.04 | Affected | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||
| c.1274C>G | T425S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, Rosetta) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -7.420 | In-Between | 0.676 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | 0.2511 | 0.2324 | 0.22 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.50 | Ambiguous | 0.63 | Ambiguous | -3.05 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||
| c.1274C>T | T425I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425I is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the balance of evidence slightly favors a pathogenic interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -10.443 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.268 | Likely Benign | 0.0827 | 0.4023 | -0.04 | Likely Benign | 0.2 | 0.07 | Likely Benign | 0.02 | Likely Benign | 0.30 | Likely Benign | -5.30 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.44 | Benign | 0.06 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.1276A>C | N426H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign; and Foldetta also predicts a benign outcome. No prediction tool is missing or inconclusive in this set. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -7.004 | In-Between | 0.248 | Likely Benign | Likely Benign | 0.237 | Likely Benign | 0.1267 | 0.3124 | 0.64 | Ambiguous | 0.0 | -0.14 | Likely Benign | 0.25 | Likely Benign | 0.24 | Likely Benign | -3.57 | Deleterious | 0.998 | Probably Damaging | 0.985 | Probably Damaging | 3.29 | Benign | 0.14 | Tolerated | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||
| c.1276A>G | N426D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Three tools (FoldX, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions (six benign vs. four pathogenic) and the two high‑accuracy benign calls suggest the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -11.159 | Likely Pathogenic | 0.554 | Ambiguous | Likely Benign | 0.173 | Likely Benign | 0.1730 | 0.1746 | 0.80 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.49 | Likely Benign | 0.64 | Ambiguous | -3.09 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.34 | Benign | 0.09 | Tolerated | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.1276A>T | N426Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two main groups: benign predictions come from REVEL, FoldX, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b. Two tools remain uncertain: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -8.510 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 0.341 | Likely Benign | 0.0578 | 0.3338 | 0.47 | Likely Benign | 0.0 | -0.50 | Ambiguous | -0.02 | Likely Benign | 0.23 | Likely Benign | -5.48 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.30 | Benign | 0.25 | Tolerated | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||
| c.1277A>C | N426T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change N426T lies in the GAP domain. It is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta remains uncertain and is not taken as evidence. Overall, the majority of tools, including the high‑accuracy methods, predict a benign effect. This consensus does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -7.389 | In-Between | 0.194 | Likely Benign | Likely Benign | 0.126 | Likely Benign | 0.1090 | 0.3002 | 0.84 | Ambiguous | 0.0 | 0.38 | Likely Benign | 0.61 | Ambiguous | 0.12 | Likely Benign | -3.14 | Deleterious | 0.983 | Probably Damaging | 0.926 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||
| c.1277A>G | N426S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and the Foldetta stability assessment is inconclusive. No evidence from FoldX or Rosetta is available. Overall, the majority of predictions support a benign impact, and this is consistent with the absence of a ClinVar assertion. Therefore, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -5.215 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.131 | Likely Benign | 0.2224 | 0.3188 | 0.81 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.67 | Ambiguous | 0.03 | Likely Benign | -2.37 | Neutral | 0.998 | Probably Damaging | 0.921 | Probably Damaging | 3.47 | Benign | 0.33 | Tolerated | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.1277A>T | N426I 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N426I has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicting pathogenicity, and Foldetta indicating a benign folding stability outcome. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -10.158 | Likely Pathogenic | 0.570 | Likely Pathogenic | Likely Benign | 0.216 | Likely Benign | 0.0656 | 0.3244 | 0.67 | Ambiguous | 0.0 | 0.14 | Likely Benign | 0.41 | Likely Benign | 0.23 | Likely Benign | -5.71 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.31 | Benign | 0.09 | Tolerated | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||
| c.1278C>A | N426K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426K resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -11.659 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 0.197 | Likely Benign | 0.1906 | 0.2822 | 0.03 | Likely Benign | 0.0 | 0.00 | Likely Benign | 0.02 | Likely Benign | 0.54 | Ambiguous | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.978 | Probably Damaging | 3.38 | Benign | 0.12 | Tolerated | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.1278C>G | N426K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N426K is located in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, while those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect on protein stability. Overall, the majority of predictions lean toward pathogenicity, with a split in the most reliable methods. Therefore, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -11.659 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 0.197 | Likely Benign | 0.1906 | 0.2822 | 0.03 | Likely Benign | 0.0 | 0.00 | Likely Benign | 0.02 | Likely Benign | 0.54 | Ambiguous | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.978 | Probably Damaging | 3.38 | Benign | 0.12 | Tolerated | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.1279C>A | H427N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H427N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, Rosetta, and AlphaMissense‑Default all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign outcome. With all available evidence pointing to a neutral effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | 1.162 | Likely Benign | 0.045 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.1507 | 0.2418 | -0.11 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.14 | Likely Benign | -0.48 | Likely Benign | 1.63 | Neutral | 0.010 | Benign | 0.006 | Benign | 3.62 | Benign | 0.46 | Tolerated | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||
| c.1279C>G | H427D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant H427D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from the available tools suggests pathogenicity, and the absence of a ClinVar classification means there is no contradiction. Therefore, based on the current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -3.684 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.163 | Likely Benign | 0.2241 | 0.1678 | 0.76 | Ambiguous | 0.1 | 1.26 | Ambiguous | 1.01 | Ambiguous | 0.10 | Likely Benign | -1.43 | Neutral | 0.677 | Possibly Damaging | 0.236 | Benign | 3.58 | Benign | 0.12 | Tolerated | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||
| c.1279C>T | H427Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H427Y missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly indicate a benign effect. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -6.824 | Likely Benign | 0.328 | Likely Benign | Likely Benign | 0.180 | Likely Benign | 0.0958 | 0.4029 | -0.08 | Likely Benign | 0.0 | -0.37 | Likely Benign | -0.23 | Likely Benign | 0.18 | Likely Benign | -3.47 | Deleterious | 0.815 | Possibly Damaging | 0.073 | Benign | 3.44 | Benign | 0.01 | Affected | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||
| c.1280A>C | H427P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H427P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Two tools are uncertain: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both indicate a pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification for H427P, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -11.098 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.324 | Likely Benign | 0.2061 | 0.3442 | 4.74 | Destabilizing | 0.1 | 7.61 | Destabilizing | 6.18 | Destabilizing | 0.68 | Ambiguous | -4.22 | Deleterious | 0.993 | Probably Damaging | 0.819 | Possibly Damaging | 3.51 | Benign | 0.01 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||
| c.1280A>G | H427R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H427R is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438185‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT, while premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign stability change. No predictions or folding results are missing or inconclusive. Overall, the majority of evidence indicates the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | 6-33438185-A-G | -3.259 | Likely Benign | 0.439 | Ambiguous | Likely Benign | 0.168 | Likely Benign | 0.2108 | 0.2121 | -0.04 | Likely Benign | 0.1 | 0.48 | Likely Benign | 0.22 | Likely Benign | 0.72 | Ambiguous | -2.61 | Deleterious | 0.174 | Benign | 0.018 | Benign | 3.51 | Benign | 0.03 | Affected | 3.38 | 25 | 0 | 2 | -1.3 | 19.05 | |||||||||||||||||||||||
| c.1280A>T | H427L 2D  3DClick to see structure in 3D Viewer AISynGAP1 H427L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: nine tools (REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while five tools (SGM‑Consensus, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy methods provide a more focused view: AlphaMissense‑Optimized indicates a benign outcome; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, remains pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Taken together, the majority of evidence supports a benign impact for H427L, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -9.691 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 0.272 | Likely Benign | 0.0942 | 0.4953 | -0.17 | Likely Benign | 0.0 | 0.05 | Likely Benign | -0.06 | Likely Benign | 0.31 | Likely Benign | -5.38 | Deleterious | 0.299 | Benign | 0.033 | Benign | 3.42 | Benign | 0.01 | Affected | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||
| c.1281T>A | H427Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 H427Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and SIFT. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect for H427Q. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -5.858 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.142 | Likely Benign | 0.1556 | 0.3382 | 0.77 | Ambiguous | 0.1 | 0.62 | Ambiguous | 0.70 | Ambiguous | 0.73 | Ambiguous | -2.41 | Neutral | 0.864 | Possibly Damaging | 0.088 | Benign | 3.52 | Benign | 0.02 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1281T>G | H427Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 H427Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and SIFT. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect for H427Q. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -5.858 | Likely Benign | 0.367 | Ambiguous | Likely Benign | 0.142 | Likely Benign | 0.1556 | 0.3382 | 0.77 | Ambiguous | 0.1 | 0.62 | Ambiguous | 0.70 | Ambiguous | 0.73 | Ambiguous | -2.41 | Neutral | 0.864 | Possibly Damaging | 0.088 | Benign | 3.52 | Benign | 0.02 | Affected | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1282T>A | Y428N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, which classifies the change as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -12.164 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.533 | Likely Pathogenic | 0.2607 | 0.0971 | 2.34 | Destabilizing | 0.0 | 3.81 | Destabilizing | 3.08 | Destabilizing | 1.85 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.03 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.1282T>C | Y428H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y428H is not reported in ClinVar but is present in gnomAD (ID 6‑33438187‑T‑C). Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score (Likely Pathogenic) all suggest a deleterious impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Consequently, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | 6-33438187-T-C | 1 | 6.19e-7 | -8.566 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.458 | Likely Benign | 0.2685 | 0.0711 | 3.18 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.69 | Destabilizing | 1.80 | Destabilizing | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 3.38 | 25 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||
| c.1282T>G | Y428D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y428D is not reported in ClinVar and is absent from gnomAD. Across a broad panel of in silico predictors, 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a deleterious effect, whereas only FATHMM classifies it as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -13.473 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.554 | Likely Pathogenic | 0.4458 | 0.1003 | 3.24 | Destabilizing | 0.0 | 4.19 | Destabilizing | 3.72 | Destabilizing | 1.64 | Destabilizing | -9.55 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.50 | Benign | 0.01 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.1283A>C | Y428S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM. All other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -10.936 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 0.505 | Likely Pathogenic | 0.4623 | 0.2352 | 3.00 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.21 | Destabilizing | 2.00 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.03 | Affected | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.1283A>G | Y428C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus result as “Likely Pathogenic,” Foldetta predicts a destabilizing, pathogenic effect, while AlphaMissense‑Optimized is uncertain. No prediction or stability result is missing; the only inconclusive outcome is the AlphaMissense‑Optimized score. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -11.312 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 0.454 | Likely Benign | 0.3322 | 0.2220 | 2.82 | Destabilizing | 0.0 | 2.99 | Destabilizing | 2.91 | Destabilizing | 2.02 | Destabilizing | -8.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.1283A>T | Y428F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b) predict a pathogenic impact. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as unavailable. Overall, the balance of evidence—five pathogenic versus three benign predictions, with a pathogenic SGM Consensus and a benign AlphaMissense‑Optimized—suggests that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -10.464 | Likely Pathogenic | 0.530 | Ambiguous | Likely Benign | 0.366 | Likely Benign | 0.2719 | 0.3146 | 0.82 | Ambiguous | 0.1 | 0.52 | Ambiguous | 0.67 | Ambiguous | 0.89 | Ambiguous | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.41 | Benign | 0.04 | Affected | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||
| c.1285C>G | R429G 2D 3DClick to see structure in 3D Viewer AISynGAP1 R429G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta’s stability analysis is uncertain. No evidence from FoldX or Rosetta is available. Overall, the predictions are evenly split, with no clear consensus. The variant is most likely of uncertain significance; it is not contradicted by ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | -9.157 | Likely Pathogenic | 0.333 | Likely Benign | Likely Benign | 0.257 | Likely Benign | 0.2888 | 0.2717 | 1.58 | Ambiguous | 0.0 | 1.68 | Ambiguous | 1.63 | Ambiguous | 1.21 | Destabilizing | -3.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.43 | Benign | 0.34 | Tolerated | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||
| c.1285C>T | R429W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429W is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438190‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; premPS and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | Conflicting | 5 | 6-33438190-C-T | 65 | 4.03e-5 | -10.666 | Likely Pathogenic | 0.500 | Ambiguous | Likely Benign | 0.282 | Likely Benign | 0.1232 | 0.3422 | 0.31 | Likely Benign | 0.1 | -0.13 | Likely Benign | 0.09 | Likely Benign | 0.52 | Ambiguous | -3.19 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 3.38 | 25 | 2 | -3 | 3.6 | 30.03 | 252.3 | 45.5 | 0.0 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg429, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or a H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, the indole ring of the Trp429 side chain cannot form ionic interactions with the acidic residues. Although it forms a H-bond with Ser471, the bonding is not as strong as that of arginine. The residue swap could affect the tertiary structure assembly during folding; however, no large-scale negative effects were seen during the simulations. | ||||||||||
| c.1286G>A | R429Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438191‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b, while premPS is inconclusive. The high‑accuracy consensus (SGM Consensus) – a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – yields a “Likely Benign” result. AlphaMissense‑Optimized itself predicts benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Taken together, the preponderance of evidence points to a benign impact for R429Q, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | Uncertain | 2 | 6-33438191-G-A | 10 | 6.20e-6 | -8.227 | Likely Pathogenic | 0.143 | Likely Benign | Likely Benign | 0.156 | Likely Benign | 0.2518 | 0.1985 | 0.45 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.41 | Likely Benign | 0.98 | Ambiguous | -1.25 | Neutral | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.47 | Benign | 0.58 | Tolerated | 3.38 | 25 | 1 | 1 | 1.0 | -28.06 | 235.8 | 59.5 | 0.0 | 0.0 | -0.3 | 0.4 | X | Potentially Pathogenic | The guanidinium group of the Arg429 side chain, located in an α helix (res. Met414-Glu436), either forms a salt bridge with the carboxylate group of an acidic residue (Asp474, Asp467) or an H-bond with the hydroxyl group of Ser471 in an opposing α helix (res. Ala461-Phe476). In the variant simulations, Gln429 cannot form ionic interactions with the acidic residues; however, the carboxamide group can form multiple H-bonds. The H-bonding coordination of the Asn429 side chain varied between the replica simulations. In one simulation, three H-bonds were formed simultaneously with the Asp467 side chain, the backbone carbonyl group of Asn426, and the amide group of Met430 at the end of the same α helix. The residue swap could affect the tertiary structure assembly during folding due to weaker bond formation, but no large-scale negative effects were seen during the simulations. | |||||||||
| c.1286G>C | R429P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; AlphaMissense‑Default and FoldX are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools and the high‑accuracy methods favor a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | -9.771 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 0.265 | Likely Benign | 0.1881 | 0.3790 | 1.53 | Ambiguous | 0.2 | 5.13 | Destabilizing | 3.33 | Destabilizing | 1.01 | Destabilizing | -2.89 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.25 | Tolerated | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||
| c.1286G>T | R429L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R429L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. No contradictory evidence is present from ClinVar or gnomAD. **Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.074921 | Structured | 0.390504 | Uncertain | 0.959 | 0.290 | 0.000 | -6.495 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.241 | Likely Benign | 0.1555 | 0.4025 | -0.05 | Likely Benign | 0.1 | 0.06 | Likely Benign | 0.01 | Likely Benign | -0.12 | Likely Benign | -1.20 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.59 | Benign | 0.37 | Tolerated | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1288A>C | M430L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Rosetta, PolyPhen‑2 (HumDiv and HumVar), SIFT, and REVEL; no tool predicts pathogenicity. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. With all available evidence pointing to a benign effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -5.873 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.107 | Likely Benign | 0.1767 | 0.5067 | 0.33 | Likely Benign | 0.1 | -0.10 | Likely Benign | 0.12 | Likely Benign | 0.72 | Ambiguous | -1.07 | Neutral | 0.028 | Benign | 0.004 | Benign | 3.69 | Benign | 0.66 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1288A>G | M430V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated changes. Only polyPhen‑2 HumDiv flags it as pathogenic, while the SGM‑Consensus score is Likely Benign. Stability‑based methods are inconclusive: FoldX and premPS return Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -3.555 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.3397 | 0.4953 | 1.48 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.63 | Ambiguous | 0.87 | Ambiguous | -1.35 | Neutral | 0.918 | Possibly Damaging | 0.185 | Benign | 3.53 | Benign | 0.51 | Tolerated | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||
| c.1288A>T | M430L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Rosetta, PolyPhen‑2 (HumDiv and HumVar), SIFT, and REVEL; no tool predicts pathogenicity. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. With all available evidence pointing to a benign effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -5.873 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.107 | Likely Benign | 0.1767 | 0.5067 | 0.33 | Likely Benign | 0.1 | -0.10 | Likely Benign | 0.12 | Likely Benign | 0.72 | Ambiguous | -1.07 | Neutral | 0.028 | Benign | 0.004 | Benign | 3.69 | Benign | 0.66 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1289T>A | M430K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and ESM1b. The remaining tools—FoldX, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors a pathogenic outcome; Foldetta remains uncertain. Overall, the majority of individual predictors lean toward a benign interpretation, whereas the SGM Consensus suggests pathogenicity. Given the lack of ClinVar evidence, there is no contradiction with existing clinical annotations. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -10.816 | Likely Pathogenic | 0.494 | Ambiguous | Likely Benign | 0.149 | Likely Benign | 0.1660 | 0.1271 | 0.78 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.61 | Ambiguous | 0.86 | Ambiguous | -2.66 | Deleterious | 0.134 | Benign | 0.033 | Benign | 3.47 | Benign | 0.32 | Tolerated | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||
| c.1289T>C | M430T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430T is reported in gnomAD (6‑33438194‑T‑C) and has no ClinVar entry. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, FoldX (uncertain), Rosetta, Foldetta (uncertain), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as benign or likely benign. No tool predicts pathogenicity. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is benign, the SGM Consensus is likely benign, and Foldetta is uncertain. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Thus, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | 6-33438194-T-C | 1 | 6.19e-7 | -3.430 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 0.2002 | 0.3184 | 1.89 | Ambiguous | 0.1 | 0.01 | Likely Benign | 0.95 | Ambiguous | 0.43 | Likely Benign | -1.48 | Neutral | 0.016 | Benign | 0.010 | Benign | 3.48 | Benign | 0.40 | Tolerated | 3.37 | 29 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||
| c.1289T>G | M430R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. The remaining tools—FoldX, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of consensus tools lean toward a benign classification, while a subset of high‑accuracy methods suggest pathogenicity, leaving the variant’s impact ambiguous. Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -10.636 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | 0.153 | Likely Benign | 0.1775 | 0.1652 | 0.98 | Ambiguous | 0.1 | 0.47 | Likely Benign | 0.73 | Ambiguous | 0.83 | Ambiguous | -2.87 | Deleterious | 0.620 | Possibly Damaging | 0.046 | Benign | 3.48 | Benign | 0.38 | Tolerated | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||
| c.1290G>A | M430I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is catalogued in gnomAD (6‑33438195‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | 6-33438195-G-A | 1 | 6.19e-7 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.068 | Likely Benign | 0.1524 | 0.4116 | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||
| c.1290G>C | M430I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining predictions (FoldX, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also classifies the variant as benign. Taken together, the consensus of both general and high‑accuracy predictors is that M430I is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.068 | Likely Benign | 0.1524 | 0.4116 | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||
| c.1290G>T | M430I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M430I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta’s combined FoldX‑MD/Rosetta output is unavailable due to the uncertain FoldX result. Overall, the evidence overwhelmingly supports a benign classification for M430I, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.385298 | Uncertain | 0.952 | 0.306 | 0.000 | -4.655 | Likely Benign | 0.420 | Ambiguous | Likely Benign | 0.068 | Likely Benign | 0.1524 | 0.4116 | 1.22 | Ambiguous | 0.1 | -0.29 | Likely Benign | 0.47 | Likely Benign | 0.65 | Ambiguous | -1.62 | Neutral | 0.134 | Benign | 0.025 | Benign | 3.54 | Benign | 0.40 | Tolerated | 3.37 | 29 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||
| c.1291C>A | L431M 2D AIThe SynGAP1 missense variant L431M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain predictions come from Rosetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and therefore unavailable. Overall, the balance of evidence, especially from the high‑accuracy tools, favors a benign classification. This conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -7.471 | In-Between | 0.375 | Ambiguous | Likely Benign | 0.102 | Likely Benign | 0.0748 | 0.3121 | 0.18 | Likely Benign | 0.3 | 0.50 | Ambiguous | 0.34 | Likely Benign | 1.07 | Destabilizing | -1.50 | Neutral | 0.995 | Probably Damaging | 0.849 | Possibly Damaging | 2.94 | Benign | 0.02 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.1291C>G | L431V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L431V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are FoldX, premPS, PROVEAN, and polyPhen‑2 HumDiv. Four tools (Rosetta, Foldetta, ESM1b, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 1‑to‑1 split between benign and pathogenic signals, and Foldetta also yields an uncertain outcome. Overall, the balance of evidence—including the higher number of benign predictions and the benign call from the most accurate tool—suggests that the variant is most likely benign. This conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -7.949 | In-Between | 0.505 | Ambiguous | Likely Benign | 0.093 | Likely Benign | 0.1377 | 0.3198 | 2.17 | Destabilizing | 0.0 | 1.50 | Ambiguous | 1.84 | Ambiguous | 1.32 | Destabilizing | -2.58 | Deleterious | 0.861 | Possibly Damaging | 0.332 | Benign | 3.04 | Benign | 0.20 | Tolerated | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||
| c.1292T>A | L431Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431Q resides in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic; this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -12.399 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.493 | Likely Benign | 0.1036 | 0.1088 | 2.69 | Destabilizing | 0.0 | 2.37 | Destabilizing | 2.53 | Destabilizing | 1.99 | Destabilizing | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.92 | Benign | 0.01 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1292T>C | L431P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431P (ClinVar ID 661045.0) is reported as Pathogenic and is not present in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the overwhelming consensus of pathogenic predictions and the ClinVar designation, the variant is most likely pathogenic, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | Likely Pathogenic | 1 | -14.222 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.659 | Likely Pathogenic | 0.3484 | 0.2163 | 6.78 | Destabilizing | 0.3 | 11.59 | Destabilizing | 9.19 | Destabilizing | 2.29 | Destabilizing | -6.39 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.91 | Benign | 0.05 | Affected | 3.37 | 29 | -3 | -3 | -5.4 | -16.04 | 222.4 | 62.8 | 0.1 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu431, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val434, Leu435, Leu696, Leu711) in the WT simulations. While the backbone amide group of Leu431 forms an H-bond with the carbonyl group of His427, the cyclic five-membered pyrrolidine ring of Pro431, lacking the necessary amide group, cannot do the same. Thus, although the cyclic five-membered pyrrolidine ring of Pro431 packs almost as favorably as the side chain of Leu431 in the hydrophobic niche, the residue swap causes the α helix to partially unfold in the variant simulations. | ||||||||||||
| c.1292T>G | L431R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -14.777 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.654 | Likely Pathogenic | 0.1191 | 0.0730 | 3.45 | Destabilizing | 0.0 | 4.76 | Destabilizing | 4.11 | Destabilizing | 1.93 | Destabilizing | -5.47 | Deleterious | 0.997 | Probably Damaging | 0.833 | Possibly Damaging | 2.93 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1294T>A | C432S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools (SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification for C432S, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -8.229 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.496 | Likely Benign | 0.4262 | 0.1415 | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.52 | Destabilizing | -9.55 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.12 | Tolerated | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.1294T>C | C432R 2D  3DClick to see structure in 3D Viewer AIClinVar has no entry for this SynGAP1 missense variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM. The majority of algorithms predict a pathogenic impact: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta report uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains inconclusive. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.858 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.690 | Likely Pathogenic | 0.1359 | 0.1766 | 1.03 | Ambiguous | 0.2 | 2.05 | Destabilizing | 1.54 | Ambiguous | 1.73 | Destabilizing | -11.46 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||
| c.1294T>G | C432G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion is consistent with the absence of a ClinVar classification; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -10.247 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.631 | Likely Pathogenic | 0.2796 | 0.2130 | 1.37 | Ambiguous | 0.0 | 2.25 | Destabilizing | 1.81 | Ambiguous | 1.60 | Destabilizing | -11.46 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.03 | Affected | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||
| c.1295G>A | C432Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant C432Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign predictions are reported by REVEL, Rosetta, FATHMM, and Foldetta. Tools with uncertain or missing results (FoldX, premPS) are not considered evidence. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predict pathogenicity, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Overall, the majority of predictions support a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.720 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.441 | Likely Benign | 0.0857 | 0.3438 | 0.62 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.47 | Likely Benign | 0.71 | Ambiguous | -10.50 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||
| c.1295G>C | C432S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools (SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification for C432S, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -8.229 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.417 | Likely Benign | 0.4262 | 0.1415 | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.52 | Destabilizing | -9.55 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.12 | Tolerated | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||
| c.1295G>T | C432F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432F is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -12.862 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.434 | Likely Benign | 0.1090 | 0.3956 | -0.44 | Likely Benign | 0.2 | -0.34 | Likely Benign | -0.39 | Likely Benign | 0.57 | Ambiguous | -10.50 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.01 | Affected | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||
| c.1296T>G | C432W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments reinforce this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus indicates a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result, providing no counter‑evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.936 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.433 | Likely Benign | 0.1217 | 0.3246 | 1.17 | Ambiguous | 0.4 | 0.72 | Ambiguous | 0.95 | Ambiguous | 0.58 | Ambiguous | -10.50 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.43 | Benign | 0.00 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||
| c.1297G>A | A433T 2D AIThe SynGAP1 A433T missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools—polyPhen‑2 HumDiv and polyPhen‑2 HumVar—predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -5.499 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.0891 | 0.5554 | 0.35 | Likely Benign | 0.5 | -0.02 | Likely Benign | 0.17 | Likely Benign | 0.40 | Likely Benign | -1.41 | Neutral | 0.964 | Probably Damaging | 0.481 | Possibly Damaging | 3.41 | Benign | 0.08 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1297G>C | A433P 2D 3DClick to see structure in 3D Viewer AISynGAP1 A433P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, SIFT, and FATHMM. Those that predict pathogenicity comprise FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. The remaining tools, premPS and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the lack of ClinVar annotation and gnomAD absence. Therefore, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -9.887 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 0.217 | Likely Benign | 0.1471 | 0.4150 | 2.48 | Destabilizing | 0.0 | 7.09 | Destabilizing | 4.79 | Destabilizing | 0.55 | Ambiguous | -2.64 | Deleterious | 0.998 | Probably Damaging | 0.820 | Possibly Damaging | 3.37 | Benign | 0.07 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1297G>T | A433S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A433S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or likely benign. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a likely benign classification; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence points to a benign impact for A433S, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -3.861 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.1938 | 0.3975 | -0.04 | Likely Benign | 0.0 | 0.41 | Likely Benign | 0.19 | Likely Benign | -0.21 | Likely Benign | 0.35 | Neutral | 0.597 | Possibly Damaging | 0.391 | Benign | 3.46 | Benign | 0.28 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1298C>A | A433E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A433E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools (premPS and AlphaMissense‑Default) give uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports benign. No prediction is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -8.210 | Likely Pathogenic | 0.506 | Ambiguous | Likely Benign | 0.148 | Likely Benign | 0.0783 | 0.1695 | -0.20 | Likely Benign | 0.0 | 0.15 | Likely Benign | -0.03 | Likely Benign | 0.58 | Ambiguous | -1.65 | Neutral | 0.998 | Probably Damaging | 0.824 | Possibly Damaging | 3.42 | Benign | 0.18 | Tolerated | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||
| c.1298C>G | A433G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A433G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. The protein‑folding stability method Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is therefore treated as unavailable evidence. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | -5.044 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.038 | Likely Benign | 0.1629 | 0.2919 | 0.59 | Ambiguous | 0.0 | 1.21 | Ambiguous | 0.90 | Ambiguous | 0.70 | Ambiguous | -1.54 | Neutral | 0.035 | Benign | 0.014 | Benign | 3.38 | Benign | 0.15 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1298C>T | A433V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A433V missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438203‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and therefore unavailable as evidence. Overall, the majority of predictions support a benign impact, and this is consistent with the lack of ClinVar pathogenic classification. Thus, the variant is most likely benign based on current computational evidence, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.098513 | Structured | 0.352258 | Uncertain | 0.938 | 0.302 | 0.000 | 6-33438203-C-T | 240 | 1.49e-4 | -8.200 | Likely Pathogenic | 0.129 | Likely Benign | Likely Benign | 0.096 | Likely Benign | 0.0753 | 0.5104 | 0.48 | Likely Benign | 0.1 | -0.07 | Likely Benign | 0.21 | Likely Benign | 0.48 | Likely Benign | -2.91 | Deleterious | 0.994 | Probably Damaging | 0.527 | Possibly Damaging | 3.43 | Benign | 0.04 | Affected | 3.37 | 29 | 0 | 0 | 2.4 | 28.05 | 214.5 | -45.8 | 0.0 | 0.0 | 0.0 | 0.2 | X | Potentially Benign | The methyl group of Ala433, located on the outer surface of an α helix (res. Met414-Glu436), does not interact with any nearby residues in the WT simulations. In the variant simulations, the iso-propyl side chain of Val433, which has a similarly hydrophobic profile as alanine, also does not form any lasting interactions at the helix surface. Accordingly, the residue swap does not negatively affect the protein structure based on the simulations. | ||||||||||||
| c.1300G>A | V434I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434I (ClinVar ID 212346.0, status Uncertain) is present in gnomAD (ID 6‑33438205‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | Uncertain | 1 | 6-33438205-G-A | 1 | 6.19e-7 | -6.999 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.192 | Likely Benign | 0.0675 | 0.3415 | -0.04 | Likely Benign | 0.0 | 0.22 | Likely Benign | 0.09 | Likely Benign | 0.31 | Likely Benign | -0.82 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.53 | Benign | 0.18 | Tolerated | 3.37 | 29 | 4 | 3 | 0.3 | 14.03 | 246.7 | -27.7 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Benign | The iso-propyl side chain of Val434, located at the end of an α helix (res. Met414-Glu436), packs against hydrophobic residues in an interhelix space (e.g., Met430, Ala707, Leu711). In the variant simulations, the sec-butyl group of Ile434 is able to form the same hydrophobic interactions. Accordingly, the residue swap does not negatively affect the protein structure based on the simulations. | |||||||||
| c.1300G>C | V434L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools, Rosetta and AlphaMissense‑Default, give uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, a protein‑folding stability method, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that V434L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -8.697 | Likely Pathogenic | 0.477 | Ambiguous | Likely Benign | 0.225 | Likely Benign | 0.0895 | 0.3813 | -0.05 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.49 | Likely Benign | 0.20 | Likely Benign | -2.30 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.64 | Benign | 0.27 | Tolerated | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||
| c.1300G>T | V434F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434F is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus predicts pathogenic; Foldetta predicts pathogenic. All predictions are available and none are inconclusive. Based on the overall distribution of predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -12.553 | Likely Pathogenic | 0.672 | Likely Pathogenic | Likely Benign | 0.417 | Likely Benign | 0.0596 | 0.3391 | 3.64 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.46 | Destabilizing | 0.27 | Likely Benign | -3.93 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.04 | Affected | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||
| c.1301T>A | V434D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign are SIFT and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and ESM1b—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized returns a pathogenic score; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among pathogenic predictors and the corroborating high‑accuracy tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -14.765 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.592 | Likely Pathogenic | 0.1307 | 0.0741 | 3.26 | Destabilizing | 0.0 | 3.33 | Destabilizing | 3.30 | Destabilizing | 1.78 | Destabilizing | -5.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.38 | Benign | 0.13 | Tolerated | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| c.1301T>C | V434A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V434A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; FoldX and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -8.531 | Likely Pathogenic | 0.441 | Ambiguous | Likely Benign | 0.238 | Likely Benign | 0.2338 | 0.2292 | 1.72 | Ambiguous | 0.0 | 2.51 | Destabilizing | 2.12 | Destabilizing | 1.00 | Destabilizing | -2.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.58 | Benign | 0.75 | Tolerated | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||
| c.1301T>G | V434G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as pathogenic. Taken together, the overwhelming majority of evidence indicates a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -12.519 | Likely Pathogenic | 0.809 | Likely Pathogenic | Ambiguous | 0.564 | Likely Pathogenic | 0.1758 | 0.2408 | 3.08 | Destabilizing | 0.0 | 4.37 | Destabilizing | 3.73 | Destabilizing | 1.91 | Destabilizing | -5.16 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.07 | Tolerated | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1303T>A | L435M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L435M missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -4.705 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.233 | Likely Benign | 0.0675 | 0.2753 | 0.24 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.63 | Ambiguous | 1.05 | Destabilizing | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.01 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||
| c.1303T>G | L435V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435V has no ClinVar assertion and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—favors pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. With the preponderance of pathogenic calls from both general and high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -7.134 | In-Between | 0.571 | Likely Pathogenic | Likely Benign | 0.217 | Likely Benign | 0.1216 | 0.2628 | 2.97 | Destabilizing | 0.1 | 2.33 | Destabilizing | 2.65 | Destabilizing | 1.36 | Destabilizing | -2.80 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.23 | Benign | 0.06 | Tolerated | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||
| c.1304T>C | L435S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -12.662 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.596 | Likely Pathogenic | 0.2705 | 0.0505 | 4.18 | Destabilizing | 0.0 | 4.09 | Destabilizing | 4.14 | Destabilizing | 1.83 | Destabilizing | -5.63 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.18 | Benign | 0.01 | Affected | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||
| c.1304T>G | L435W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L435W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM. The majority of other in silico predictors (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic, and the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the computational evidence strongly favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | Uncertain | 1 | -14.889 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.572 | Likely Pathogenic | 0.0536 | 0.2496 | 2.11 | Destabilizing | 0.1 | 0.69 | Ambiguous | 1.40 | Ambiguous | 1.66 | Destabilizing | -5.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 3.37 | 29 | -2 | -2 | -4.7 | 73.05 | 242.2 | -25.2 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The iso-butyl side chain of Leu435, located in an α helix (res. Met414-Glu436), packs against other hydrophobic residues in an interhelix space (e.g., Val699, Val447, Leu489, Leu439) in the WT simulations. In the variant simulations, the indole ring of Trp435 fits into the same niche despite its considerably bulkier size. Additionally, the side chain forms an H-bond with the backbone carbonyl of Leu696 in an α helix (res. Asp684-Gln702). Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | ||||||||||||
| c.1305G>C | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of any ClinVar annotation to contradict this assessment, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | 0.0587 | 0.2723 | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1305G>T | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (Likely Pathogenic). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | 0.0587 | 0.2723 | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1306G>A | E436K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining evaluated algorithms (REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a pathogenic impact; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E436K, which does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | Uncertain | 1 | -13.869 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.829 | Likely Pathogenic | 0.2332 | 0.5995 | 0.56 | Ambiguous | 0.1 | 2.86 | Destabilizing | 1.71 | Ambiguous | 0.82 | Ambiguous | -3.77 | Deleterious | 0.994 | Probably Damaging | 0.951 | Probably Damaging | 4.71 | Benign | 0.02 | Affected | 3.37 | 29 | 0 | 1 | -0.4 | -0.94 | 186.8 | 39.8 | 0.0 | 0.0 | -0.2 | 0.0 | X | X | X | Potentially Pathogenic | The carboxylate group of Glu436, located on the α helix (res. Met414-Glu436), forms a salt bridge with the amino group of the Lys444 side chain on an opposing α helix (res. Val441-Ser457). The backbone carbonyl of Glu436 also H-bonds with the Lys444 side chain, which helps keep the ends of the two α helices tightly connected. In contrast, in the variant simulations, the salt bridge formation with Lys444 is not possible. Instead, the repelled Lys436 side chain rotates outward, causing a change in the α helix backbone H-bonding: the amide group of Lys444 H-bonds with the carbonyl of Ala433 instead of the carbonyl of Cys432. | ||||||||||
| c.1306G>C | E436Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436Q is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the consensus of pathogenic predictions outweighs benign ones, and the high‑accuracy tools reinforce a pathogenic classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.413 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.607 | Likely Pathogenic | 0.1237 | 0.5809 | 0.51 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.05 | Ambiguous | 0.50 | Likely Benign | -2.76 | Deleterious | 0.992 | Probably Damaging | 0.946 | Probably Damaging | 4.64 | Benign | 0.01 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1307A>C | E436A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436A is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include Foldetta, premPS, and FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. Two high‑accuracy predictors give concordant results: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. No prediction is missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for E436A, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.678 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.825 | Likely Pathogenic | 0.3901 | 0.5116 | 1.03 | Ambiguous | 0.0 | -0.88 | Ambiguous | 0.08 | Likely Benign | 0.23 | Likely Benign | -5.68 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 4.65 | Benign | 0.05 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1307A>G | E436G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, premPS, and Foldetta are inconclusive. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta’s stability prediction is uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.355 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.802 | Likely Pathogenic | 0.2910 | 0.4841 | 1.50 | Ambiguous | 0.1 | 2.02 | Destabilizing | 1.76 | Ambiguous | 0.58 | Ambiguous | -6.63 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 4.61 | Benign | 0.03 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1307A>T | E436V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436V variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include premPS and FATHMM, while the remaining evaluated algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -13.364 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.875 | Likely Pathogenic | 0.0727 | 0.5952 | 1.45 | Ambiguous | 0.0 | 1.62 | Ambiguous | 1.54 | Ambiguous | 0.30 | Likely Benign | -6.63 | Deleterious | 0.995 | Probably Damaging | 0.967 | Probably Damaging | 4.64 | Benign | 0.03 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1308G>C | E436D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are limited to FATHMM, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic (3 pathogenic vs. 1 benign). Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -10.355 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.554 | Likely Pathogenic | 0.1938 | 0.3553 | 0.55 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.63 | Ambiguous | 0.73 | Ambiguous | -2.85 | Deleterious | 0.986 | Probably Damaging | 0.921 | Probably Damaging | 4.61 | Benign | 0.01 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1308G>T | E436D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are limited to FATHMM, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic (3 pathogenic vs. 1 benign). Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -10.355 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.554 | Likely Pathogenic | 0.1938 | 0.3553 | 0.55 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.63 | Ambiguous | 0.73 | Ambiguous | -2.85 | Deleterious | 0.986 | Probably Damaging | 0.921 | Probably Damaging | 4.61 | Benign | 0.01 | Affected | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1309C>A | P437T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P437T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta yielding an uncertain stability change. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.011 | Likely Pathogenic | 0.484 | Ambiguous | Likely Benign | 0.305 | Likely Benign | 0.1659 | 0.5782 | 1.35 | Ambiguous | 0.0 | -3.46 | Stabilizing | -1.06 | Ambiguous | 0.54 | Ambiguous | -6.67 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||
| c.1309C>G | P437A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P437A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, Rosetta, FATHMM, AlphaMissense‑Optimized, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Tools with uncertain or inconclusive results are AlphaMissense‑Default, FoldX, and Foldetta. High‑accuracy assessments give AlphaMissense‑Optimized a benign prediction. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (pathogenic), yields a pathogenic consensus. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the balance of evidence leans toward a pathogenic effect for P437A, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -12.059 | Likely Pathogenic | 0.392 | Ambiguous | Likely Benign | 0.266 | Likely Benign | 0.3489 | 0.4775 | 1.23 | Ambiguous | 0.0 | -3.14 | Stabilizing | -0.96 | Ambiguous | 0.50 | Likely Benign | -6.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||
| c.1309C>T | P437S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P437S is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33438214‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome; the remaining methods (FoldX, Foldetta, premPS, AlphaMissense‑Default) are uncertain and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic interpretation. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | 6-33438214-C-T | 2 | 1.24e-6 | -11.964 | Likely Pathogenic | 0.518 | Ambiguous | Likely Benign | 0.226 | Likely Benign | 0.3548 | 0.4843 | 1.14 | Ambiguous | 0.0 | -3.31 | Stabilizing | -1.09 | Ambiguous | 0.60 | Ambiguous | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.49 | Benign | 0.01 | Affected | 3.38 | 26 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||
| c.1310C>A | P437H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P437H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the balance of evidence favors a pathogenic classification for P437H, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.496 | Likely Pathogenic | 0.826 | Likely Pathogenic | Ambiguous | 0.343 | Likely Benign | 0.1819 | 0.4328 | 1.19 | Ambiguous | 0.0 | -3.28 | Stabilizing | -1.05 | Ambiguous | 0.31 | Likely Benign | -7.75 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.44 | Benign | 0.01 | Affected | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||
| c.1310C>G | P437R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P437R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With the majority of tools indicating pathogenicity and the high‑accuracy consensus leaning toward pathogenic, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.094 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | 0.461 | Likely Benign | 0.1448 | 0.2846 | 0.34 | Likely Benign | 0.1 | -3.52 | Stabilizing | -1.59 | Ambiguous | 0.61 | Ambiguous | -7.72 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||
| c.1310C>T | P437L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P437L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or uncertain are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta are uncertain. Taken together, the majority of evidence points toward a pathogenic impact for P437L, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.554 | Likely Pathogenic | 0.787 | Likely Pathogenic | Ambiguous | 0.324 | Likely Benign | 0.2228 | 0.6354 | 1.10 | Ambiguous | 0.0 | -3.52 | Stabilizing | -1.21 | Ambiguous | 0.35 | Likely Benign | -8.48 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.67 | Benign | 0.04 | Affected | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||
| c.1312G>A | A438T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (gnomAD ID 6‑33438217‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status of “Uncertain.” Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | Conflicting | 3 | 6-33438217-G-A | 16 | 9.91e-6 | -5.339 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.021 | Likely Benign | 0.0999 | 0.5574 | 0.21 | Likely Benign | 0.0 | -0.07 | Likely Benign | 0.07 | Likely Benign | 0.36 | Likely Benign | -0.81 | Neutral | 0.300 | Benign | 0.011 | Benign | 4.18 | Benign | 0.14 | Tolerated | 3.38 | 26 | 1 | 0 | -2.5 | 30.03 | 214.2 | -42.7 | -0.3 | 0.1 | -0.4 | 0.1 | X | Potentially Benign | The methyl group of Ala438, located in a four-residue loop connecting two α helices (res. Asn440-Thr458 and Pro413-Glu436), packs against hydrophobic residues from a nearby α helix or loop residues (e.g., Leu703, Val699). In the variant simulations, the methyl group of Thr438 is able to establish similar hydrophobic packing. Moreover, the hydroxyl group also H-bonds with nearby residues, such as the carbonyl group of the neighboring loop residue Pro437. Accordingly, the residue swap does not generate an apparent negative effect on the protein structure based on the simulations. | |||||||||
| c.1312G>C | A438P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A438P missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic impact are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv), SIFT, and AlphaMissense‑Default; premPS and ESM1b are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, six tools predict pathogenicity versus four predicting benign, and the high‑accuracy consensus is split, but the majority of evidence points toward a deleterious effect. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -7.955 | In-Between | 0.721 | Likely Pathogenic | Likely Benign | 0.158 | Likely Benign | 0.1624 | 0.4150 | 2.21 | Destabilizing | 0.1 | 6.36 | Destabilizing | 4.29 | Destabilizing | 0.83 | Ambiguous | -2.46 | Neutral | 0.815 | Possibly Damaging | 0.137 | Benign | 4.09 | Benign | 0.05 | Affected | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||
| c.1312G>T | A438S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. The only inconclusive results come from Rosetta and premPS, which are listed as uncertain. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Overall, the evidence strongly supports a benign effect, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -6.085 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.012 | Likely Benign | 0.2143 | 0.3995 | 0.30 | Likely Benign | 0.0 | 0.62 | Ambiguous | 0.46 | Likely Benign | 0.68 | Ambiguous | -1.27 | Neutral | 0.042 | Benign | 0.035 | Benign | 4.14 | Benign | 0.15 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1313C>A | A438D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A438D missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is also inconclusive. Overall, the majority of evidence points toward a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Thus, based on the available predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -7.410 | In-Between | 0.808 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | 0.1490 | 0.1941 | 1.60 | Ambiguous | 0.1 | 0.70 | Ambiguous | 1.15 | Ambiguous | 0.92 | Ambiguous | -3.07 | Deleterious | 0.859 | Possibly Damaging | 0.124 | Benign | 4.10 | Benign | 0.04 | Affected | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||
| c.1313C>G | A438G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only PROVEAN predicts a pathogenic outcome. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for A438G, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | -5.790 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 0.1788 | 0.2719 | 1.08 | Ambiguous | 0.1 | 1.78 | Ambiguous | 1.43 | Ambiguous | 0.80 | Ambiguous | -2.51 | Deleterious | 0.247 | Benign | 0.037 | Benign | 4.12 | Benign | 0.11 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1313C>T | A438V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A438V is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (gnomAD ID 6‑33438218‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign”; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive (Uncertain). Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.147574 | Structured | 0.290154 | Uncertain | 0.929 | 0.293 | 0.000 | 6-33438218-C-T | 3 | 1.86e-6 | 1.405 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.0904 | 0.5292 | -0.36 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.53 | Ambiguous | -1.21 | Stabilizing | 1.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.45 | Benign | 0.97 | Tolerated | 3.38 | 26 | 0 | 0 | 2.4 | 28.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||
| c.1315C>A | L439M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L439M is reported in gnomAD (variant ID 6‑33438220‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on benign impact include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 (HumDiv and HumVar) and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as inconclusive. Overall, the majority of evidence points to a benign effect; there is no ClinVar classification to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | 6-33438220-C-A | 1 | 6.20e-7 | -5.840 | Likely Benign | 0.363 | Ambiguous | Likely Benign | 0.187 | Likely Benign | 0.0720 | 0.2753 | -0.33 | Likely Benign | 0.1 | 1.34 | Ambiguous | 0.51 | Ambiguous | 1.01 | Destabilizing | -1.43 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 3.38 | 25 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||
| c.1315C>G | L439V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; premPS is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions (8 benign vs. 5 pathogenic) favor a benign classification, and this consensus does not contradict the absence of ClinVar evidence. Thus, based on current computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -6.340 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.121 | Likely Benign | 0.1272 | 0.2628 | 2.34 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.37 | Destabilizing | 0.91 | Ambiguous | -1.13 | Neutral | 0.976 | Probably Damaging | 0.941 | Probably Damaging | 3.36 | Benign | 0.12 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1316T>A | L439Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -11.162 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.575 | Likely Pathogenic | 0.1065 | 0.0488 | 2.50 | Destabilizing | 0.1 | 2.06 | Destabilizing | 2.28 | Destabilizing | 1.35 | Destabilizing | -5.15 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1316T>C | L439P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -9.929 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.539 | Likely Pathogenic | 0.3426 | 0.1192 | 6.30 | Destabilizing | 0.2 | 7.62 | Destabilizing | 6.96 | Destabilizing | 1.28 | Destabilizing | -5.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.02 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1316T>G | L439R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L439R lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact; FoldX is uncertain and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -12.870 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.554 | Likely Pathogenic | 0.1217 | 0.0488 | 1.90 | Ambiguous | 0.5 | 2.62 | Destabilizing | 2.26 | Destabilizing | 1.40 | Destabilizing | -5.25 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.22 | Benign | 0.01 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1318A>C | N440H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and ESM1b, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -8.064 | Likely Pathogenic | 0.226 | Likely Benign | Likely Benign | 0.140 | Likely Benign | 0.0935 | 0.3270 | 1.12 | Ambiguous | 0.1 | 0.83 | Ambiguous | 0.98 | Ambiguous | 0.00 | Likely Benign | -2.48 | Neutral | 0.835 | Possibly Damaging | 0.217 | Benign | 3.40 | Benign | 0.19 | Tolerated | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||
| c.1318A>G | N440D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -9.335 | Likely Pathogenic | 0.407 | Ambiguous | Likely Benign | 0.074 | Likely Benign | 0.1544 | 0.2025 | -0.62 | Ambiguous | 0.0 | -0.41 | Likely Benign | -0.52 | Ambiguous | 0.47 | Likely Benign | -1.71 | Neutral | 0.229 | Benign | 0.045 | Benign | 3.43 | Benign | 0.43 | Tolerated | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.1318A>T | N440Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yielding an uncertain stability change. Overall, the majority of predictions lean toward a benign interpretation, and this is consistent with the lack of ClinVar annotation. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.586 | Likely Pathogenic | 0.674 | Likely Pathogenic | Likely Benign | 0.135 | Likely Benign | 0.0535 | 0.3624 | 0.81 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.03 | Ambiguous | 0.20 | Likely Benign | -3.81 | Deleterious | 0.931 | Possibly Damaging | 0.230 | Benign | 3.43 | Benign | 0.07 | Tolerated | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||
| c.1319A>C | N440T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly favor a benign effect: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, REVEL, premPS, Rosetta, Foldetta, and the SGM‑Consensus (majority vote) all predict benign or likely benign. No tool predicts pathogenicity; the only inconclusive result is from FoldX, which is listed as uncertain. High‑accuracy methods corroborate the benign assessment: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Therefore, based on the available predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -5.371 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.0969 | 0.3341 | 0.58 | Ambiguous | 0.0 | 0.16 | Likely Benign | 0.37 | Likely Benign | 0.11 | Likely Benign | -1.27 | Neutral | 0.007 | Benign | 0.005 | Benign | 3.48 | Benign | 0.14 | Tolerated | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||
| c.1319A>G | N440S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or likely benign. Only FoldX and premPS returned uncertain results, which are treated as unavailable. High‑accuracy methods corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -1.753 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.104 | Likely Benign | 0.2024 | 0.3556 | 0.52 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.30 | Likely Benign | -0.50 | Ambiguous | 1.15 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.53 | Benign | 0.92 | Tolerated | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.1319A>T | N440I 2D AISynGAP1 missense variant N440I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta remains inconclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.365 | Likely Pathogenic | 0.778 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | 0.0554 | 0.3772 | 0.97 | Ambiguous | 0.9 | 1.10 | Ambiguous | 1.04 | Ambiguous | 0.10 | Likely Benign | -4.07 | Deleterious | 0.322 | Benign | 0.109 | Benign | 3.47 | Benign | 0.03 | Affected | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||
| c.1320T>A | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.058 | Likely Benign | 0.1660 | 0.2550 | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1320T>G | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.057 | Likely Benign | 0.1660 | 0.2550 | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1321G>A | V441I 2D AIThe SynGAP1 missense variant V441I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only ESM1b predicts it as pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. No contradictory evidence is present. Based on the collective predictions, the variant is most likely benign, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -8.773 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.135 | Likely Benign | 0.0694 | 0.3412 | -0.24 | Likely Benign | 0.3 | 0.11 | Likely Benign | -0.07 | Likely Benign | 0.25 | Likely Benign | -0.82 | Neutral | 0.287 | Benign | 0.038 | Benign | 3.41 | Benign | 0.16 | Tolerated | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||
| c.1321G>C | V441L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V441L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the preponderance of evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -9.546 | Likely Pathogenic | 0.395 | Ambiguous | Likely Benign | 0.135 | Likely Benign | 0.0961 | 0.3881 | -0.43 | Likely Benign | 0.0 | 0.59 | Ambiguous | 0.08 | Likely Benign | 0.45 | Likely Benign | -2.27 | Neutral | 0.165 | Benign | 0.028 | Benign | 3.43 | Benign | 0.11 | Tolerated | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||
| c.1321G>T | V441F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V441F missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools lean toward a benign interpretation, and the high‑accuracy predictions are split but favor benign. Thus, the variant is most likely benign based on current computational evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -13.519 | Likely Pathogenic | 0.653 | Likely Pathogenic | Likely Benign | 0.355 | Likely Benign | 0.0670 | 0.3269 | -0.26 | Likely Benign | 0.0 | 0.32 | Likely Benign | 0.03 | Likely Benign | 0.54 | Ambiguous | -4.22 | Deleterious | 0.992 | Probably Damaging | 0.658 | Possibly Damaging | 3.37 | Benign | 0.08 | Tolerated | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||
| c.1322T>A | V441D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V441D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and Foldetta, whereas a majority of tools (SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. FoldX and Rosetta are inconclusive, and AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while Foldetta predicts benign stability. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -15.392 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.308 | Likely Benign | 0.1232 | 0.0698 | -0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | -0.01 | Likely Benign | 1.15 | Destabilizing | -6.07 | Deleterious | 1.000 | Probably Damaging | 0.959 | Probably Damaging | 3.38 | Benign | 0.10 | Tolerated | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| c.1322T>C | V441A 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V441A is listed in ClinVar as uncertain and is present in gnomAD (ID 6‑33438227‑T‑C). Consensus from most in silico predictors favors a benign effect: REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized all report benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and ESM1b, while premPS and AlphaMissense‑Default remain uncertain. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports benign. Overall, the preponderance of evidence points to a benign impact, aligning with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | Conflicting | 2 | 6-33438227-T-C | 3 | 1.86e-6 | -9.439 | Likely Pathogenic | 0.359 | Ambiguous | Likely Benign | 0.053 | Likely Benign | 0.2390 | 0.1800 | -0.14 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.10 | Likely Benign | 0.95 | Ambiguous | -2.92 | Deleterious | 0.513 | Possibly Damaging | 0.214 | Benign | 3.44 | Benign | 0.93 | Tolerated | 3.37 | 29 | 0 | 0 | -2.4 | -28.05 | 195.0 | 44.6 | 0.0 | 0.1 | 0.5 | 0.0 | X | X | Uncertain | The iso-propyl side chain of Val441, located on the outer surface of an α helix (res. Asn440-Thr458), does not interact with other residues in the WT simulations. In the variant simulations, the methyl side chain of Ala441 is similarly hydrophobic and does not form any interactions on the outer helix surface. Although the residue swap does not negatively affect the protein structure based on the simulations, it is noteworthy that the residue faces the RasGTPase interface. Thus, the effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||
| c.1322T>G | V441G 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V441G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; the remaining tools (Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence points to a benign effect, but the SGM Consensus and several individual pathogenic predictors introduce uncertainty. Therefore, the variant is most likely benign based on the overall prediction landscape, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -12.380 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.273 | Likely Benign | 0.1664 | 0.1715 | 0.18 | Likely Benign | 0.0 | 1.25 | Ambiguous | 0.72 | Ambiguous | 0.95 | Ambiguous | -5.88 | Deleterious | 0.841 | Possibly Damaging | 0.997 | Probably Damaging | 3.41 | Benign | 0.24 | Tolerated | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1324A>C | K442Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K442Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -10.410 | Likely Pathogenic | 0.562 | Ambiguous | Likely Benign | 0.268 | Likely Benign | 0.3353 | 0.1014 | 0.05 | Likely Benign | 0.1 | 0.03 | Likely Benign | 0.04 | Likely Benign | 0.25 | Likely Benign | -3.10 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.39 | Benign | 0.18 | Tolerated | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||
| c.1324A>G | K442E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K442E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized remains uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No single evidence decisively outweighs the others. Therefore, the variant’s pathogenicity remains uncertain; the predictions do not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -12.813 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.324 | Likely Benign | 0.2943 | 0.0789 | -0.05 | Likely Benign | 0.1 | -0.21 | Likely Benign | -0.13 | Likely Benign | 0.24 | Likely Benign | -3.34 | Deleterious | 0.997 | Probably Damaging | 0.966 | Probably Damaging | 3.47 | Benign | 0.16 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1325A>C | K442T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K442T missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign stability change; AlphaMissense‑Optimized remains inconclusive. Overall, the predictions are evenly split, with no single consensus. Thus, the variant is most likely benign based on the majority of evidence, and this assessment does not contradict any ClinVar record (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -11.273 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.330 | Likely Benign | 0.1510 | 0.2859 | 0.30 | Likely Benign | 0.2 | 0.21 | Likely Benign | 0.26 | Likely Benign | 0.22 | Likely Benign | -5.01 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.43 | Benign | 0.07 | Tolerated | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1325A>G | K442R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K442R is catalogued in gnomAD (ID 6‑33438230‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tools predicting a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | 6-33438230-A-G | 1 | 6.20e-7 | -5.761 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.098 | Likely Benign | 0.3885 | 0.0778 | 0.13 | Likely Benign | 0.1 | 0.29 | Likely Benign | 0.21 | Likely Benign | 0.51 | Ambiguous | -1.42 | Neutral | 0.972 | Probably Damaging | 0.875 | Possibly Damaging | 3.46 | Benign | 0.35 | Tolerated | 3.37 | 29 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||
| c.1325A>T | K442I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K442I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy assessments are: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions, including the two high‑accuracy pathogenic calls, indicate a pathogenic impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -14.921 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.350 | Likely Benign | 0.0943 | 0.3073 | 0.16 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.00 | Likely Benign | 0.30 | Likely Benign | -6.91 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.02 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.1326A>C | K442N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K442N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta (which integrates FoldX‑MD and Rosetta outputs). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, but the presence of several strong benign predictions and a benign folding‑stability result introduces uncertainty. Based on the current computational evidence, the variant is most likely pathogenic, and this does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -11.039 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.161 | Likely Benign | 0.2686 | 0.1314 | 0.37 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.31 | Likely Benign | -4.05 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.10 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1326A>T | K442N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K442N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta (which integrates FoldX‑MD and Rosetta outputs). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, but the presence of several strong benign predictions and a benign folding‑stability result introduces uncertainty. Based on the current computational evidence, the variant is most likely pathogenic, and this does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.255766 | Uncertain | 0.912 | 0.225 | 0.000 | -11.039 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.161 | Likely Benign | 0.2686 | 0.1314 | 0.37 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.31 | Likely Benign | -4.05 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.10 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1327G>A | G443S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as benign. Only Rosetta and premPS yield uncertain results, which are treated as unavailable. Grouping by consensus, the benign‑predicting tools outnumber any pathogenic calls (none). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Therefore, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -1.258 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 0.2409 | 0.3416 | 0.25 | Likely Benign | 0.1 | -0.72 | Ambiguous | -0.24 | Likely Benign | -0.65 | Ambiguous | 0.40 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.51 | Benign | 0.34 | Tolerated | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||
| c.1327G>C | G443R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM all classify it as benign. Only two tools predict pathogenicity: polyPhen‑2 HumDiv and AlphaMissense‑Default. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are treated as unavailable. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments are: AlphaMissense‑Optimized (uncertain), SGM Consensus (likely benign), and Foldetta (uncertain). Overall, the preponderance of evidence points to a benign impact for G443R, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -6.954 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | 0.0934 | 0.3197 | -0.88 | Ambiguous | 0.3 | -1.19 | Ambiguous | -1.04 | Ambiguous | 0.28 | Likely Benign | -1.49 | Neutral | 0.832 | Possibly Damaging | 0.286 | Benign | 3.40 | Benign | 0.21 | Tolerated | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.1327G>T | G443C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The remaining tools are inconclusive: Foldetta is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta remains uncertain. Overall, the consensus of the majority of evidence points to a benign impact for G443C, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -4.308 | Likely Benign | 0.208 | Likely Benign | Likely Benign | 0.260 | Likely Benign | 0.1258 | 0.2782 | -0.06 | Likely Benign | 0.0 | -0.95 | Ambiguous | -0.51 | Ambiguous | -0.10 | Likely Benign | -2.94 | Deleterious | 0.977 | Probably Damaging | 0.504 | Possibly Damaging | 3.37 | Benign | 0.16 | Tolerated | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||
| c.1328G>A | G443D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. Uncertain results come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as inconclusive. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. The variant is most likely benign based on the current predictive landscape. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -6.818 | Likely Benign | 0.761 | Likely Pathogenic | Likely Benign | 0.072 | Likely Benign | 0.1687 | 0.2090 | -0.19 | Likely Benign | 0.2 | -1.72 | Ambiguous | -0.96 | Ambiguous | 0.32 | Likely Benign | -0.50 | Neutral | 0.345 | Benign | 0.072 | Benign | 3.63 | Benign | 0.43 | Tolerated | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||
| c.1328G>C | G443A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. The protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is therefore treated as unavailable evidence. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -0.332 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.3539 | 0.3192 | -0.59 | Ambiguous | 0.1 | -1.61 | Ambiguous | -1.10 | Ambiguous | -0.52 | Ambiguous | -1.04 | Neutral | 0.022 | Benign | 0.011 | Benign | 3.41 | Benign | 0.54 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1328G>T | G443V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. Overall, the majority of evidence points to a benign impact for G443V, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -4.130 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.1089 | 0.3375 | 0.17 | Likely Benign | 0.2 | -2.19 | Stabilizing | -1.01 | Ambiguous | 0.21 | Likely Benign | -2.90 | Deleterious | 0.585 | Possibly Damaging | 0.195 | Benign | 3.36 | Benign | 0.12 | Tolerated | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| c.1330A>C | K444Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K444Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K444Q, and this conclusion does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -12.876 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.382 | Likely Benign | 0.4112 | 0.1057 | 1.34 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.35 | Ambiguous | 1.04 | Destabilizing | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.43 | Benign | 0.07 | Tolerated | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.1330A>G | K444E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K444E missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated predictors—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -15.571 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.437 | Likely Benign | 0.3486 | 0.0793 | 2.99 | Destabilizing | 0.1 | 3.75 | Destabilizing | 3.37 | Destabilizing | 1.10 | Destabilizing | -3.82 | Deleterious | 0.997 | Probably Damaging | 0.981 | Probably Damaging | 3.40 | Benign | 0.01 | Affected | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1331A>C | K444T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Foldetta, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain (treated as unavailable for pathogenicity inference). Overall, the majority of reliable predictions indicate a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -15.557 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | 0.1643 | 0.3416 | 2.12 | Destabilizing | 0.1 | 1.17 | Ambiguous | 1.65 | Ambiguous | 0.96 | Ambiguous | -5.73 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1331A>G | K444R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K444R is not reported in ClinVar and has no gnomAD allele. Prediction tools cluster into benign (REVEL, FoldX, SIFT, FATHMM, AlphaMissense‑Optimized) and pathogenic (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Two tools (Rosetta, premPS) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing. Overall, six tools favor pathogenicity while five favor benignity, and the high‑accuracy consensus leans toward benign. Thus the variant is most likely pathogenic based on the broader set of predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -10.753 | Likely Pathogenic | 0.693 | Likely Pathogenic | Likely Benign | 0.213 | Likely Benign | 0.4597 | 0.0972 | -0.12 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.37 | Likely Benign | 0.77 | Ambiguous | -2.86 | Deleterious | 0.972 | Probably Damaging | 0.926 | Probably Damaging | 3.45 | Benign | 0.12 | Tolerated | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.1331A>T | K444M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are returned by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further highlight the discrepancy: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Overall, the majority of tools lean toward a pathogenic interpretation, and this is not contradicted by any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.223 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | 0.0934 | 0.3890 | 0.39 | Likely Benign | 0.1 | -0.47 | Likely Benign | -0.04 | Likely Benign | 0.33 | Likely Benign | -5.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.41 | Benign | 0.00 | Affected | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||
| c.1332G>C | K444N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta’s stability assessment is uncertain and therefore not used as evidence. Overall, the preponderance of evidence points to a pathogenic effect for K444N. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.797 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.286 | Likely Benign | 0.3282 | 0.1213 | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1332G>T | K444N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that predict a pathogenic effect include FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.797 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.286 | Likely Benign | 0.3282 | 0.1213 | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1333G>A | E445K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E445K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic calls arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence—including the high‑accuracy tools—supports a pathogenic effect. This conclusion does not conflict with ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -15.371 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.524 | Likely Pathogenic | 0.1784 | 0.5311 | 0.02 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.02 | Likely Benign | 0.46 | Likely Benign | -3.82 | Deleterious | 0.991 | Probably Damaging | 0.951 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1333G>C | E445Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445Q is reported in gnomAD (ID 6‑33438238‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b). Two tools remain inconclusive (premPS, AlphaMissense‑Optimized). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign impact. Overall, the balance of evidence tilts toward pathogenicity, with the high‑accuracy consensus supporting this view, and there is no conflict with ClinVar status because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | 6-33438238-G-C | 1 | 6.19e-7 | -12.430 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 0.240 | Likely Benign | 0.0787 | 0.5018 | -0.03 | Likely Benign | 0.0 | 0.20 | Likely Benign | 0.09 | Likely Benign | 0.70 | Ambiguous | -2.86 | Deleterious | 0.987 | Probably Damaging | 0.946 | Probably Damaging | 3.40 | Benign | 0.12 | Tolerated | 3.38 | 31 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||
| c.1334A>C | E445A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as Benign. Overall, the majority of predictions lean toward pathogenicity, and the high‑accuracy consensus supports a likely pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -12.659 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.476 | Likely Benign | 0.2846 | 0.4876 | 0.09 | Likely Benign | 0.0 | -0.34 | Likely Benign | -0.13 | Likely Benign | 0.56 | Ambiguous | -5.73 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1334A>G | E445G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Predictions that are inconclusive or uncertain are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E445G, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -12.294 | Likely Pathogenic | 0.823 | Likely Pathogenic | Ambiguous | 0.523 | Likely Pathogenic | 0.2446 | 0.4202 | 0.80 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.80 | Ambiguous | 0.69 | Ambiguous | -6.68 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1334A>T | E445V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of evidence points toward a pathogenic effect. The variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -14.830 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.572 | Likely Pathogenic | 0.0414 | 0.5233 | 0.34 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.17 | Likely Benign | 0.32 | Likely Benign | -6.68 | Deleterious | 0.992 | Probably Damaging | 0.967 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1335G>C | E445D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445D is reported in gnomAD (ID 6‑33438240‑G‑C) but has no ClinVar entry. Functional prediction tools show a split verdict: benign calls come from REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence, especially the SGM Consensus, points to a pathogenic effect for E445D. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | 6-33438240-G-C | 4 | 2.48e-6 | -10.238 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.136 | Likely Benign | 0.1437 | 0.3526 | 0.81 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.65 | Ambiguous | 0.91 | Ambiguous | -2.86 | Deleterious | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.54 | Benign | 0.09 | Tolerated | 3.38 | 31 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||
| c.1335G>T | E445D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E445D is not reported in ClinVar (status: none) and is absent from gnomAD. Prediction tools that agree on benign include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized; those that agree on pathogenic include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or unavailable results come from FoldX, Foldetta, and premPS. High‑accuracy methods give a split view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta is uncertain. Overall, the predictions are inconclusive, with an equal number of benign and pathogenic calls. Thus, the variant is most likely benign based on the current evidence, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -10.238 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.136 | Likely Benign | 0.1437 | 0.3526 | 0.81 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.65 | Ambiguous | 0.91 | Ambiguous | -2.86 | Deleterious | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.54 | Benign | 0.09 | Tolerated | 3.38 | 31 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||
| c.1336G>A | E446K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E446K is not reported in ClinVar (ClinVar status: not present) and is found in gnomAD (ID 6‑33438241‑G‑A). Prediction tools that agree on a benign effect include only FATHMM. Tools that agree on a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote). Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy methods give the following: AlphaMissense‑Optimized is uncertain; SGM‑Consensus indicates likely pathogenic; Foldetta is uncertain. Overall, the majority of evidence points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | 6-33438241-G-A | 1 | 6.19e-7 | -14.140 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.518 | Likely Pathogenic | 0.2141 | 0.6511 | 0.80 | Ambiguous | 0.4 | 1.57 | Ambiguous | 1.19 | Ambiguous | 0.81 | Ambiguous | -3.75 | Deleterious | 0.994 | Probably Damaging | 0.975 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 3.38 | 31 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||
| c.1336G>C | E446Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E446Q missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability predictions are available. Overall, the balance of evidence from the consensus of multiple in silico predictors points to a pathogenic classification for E446Q. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -11.107 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 0.337 | Likely Benign | 0.1049 | 0.6218 | 0.92 | Ambiguous | 0.5 | 0.54 | Ambiguous | 0.73 | Ambiguous | 0.84 | Ambiguous | -2.80 | Deleterious | 0.992 | Probably Damaging | 0.973 | Probably Damaging | 3.24 | Benign | 0.04 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1337A>C | E446A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E446A is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Predictors that classify it as pathogenic comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yielded an inconclusive result and is treated as unavailable. Overall, the majority of predictions lean toward pathogenicity, and this conclusion is not contradicted by the absence of a ClinVar entry. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -9.868 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.443 | Likely Benign | 0.3195 | 0.5877 | 1.66 | Ambiguous | 0.7 | 0.39 | Likely Benign | 1.03 | Ambiguous | 0.67 | Ambiguous | -5.60 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1337A>G | E446G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E446G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM. The majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -11.457 | Likely Pathogenic | 0.866 | Likely Pathogenic | Ambiguous | 0.510 | Likely Pathogenic | 0.2665 | 0.5202 | 2.62 | Destabilizing | 0.7 | 1.63 | Ambiguous | 2.13 | Destabilizing | 0.83 | Ambiguous | -6.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1337A>T | E446V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E446V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (8 pathogenic vs. 3 benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -12.231 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.513 | Likely Pathogenic | 0.0618 | 0.6433 | 1.72 | Ambiguous | 0.7 | 0.34 | Likely Benign | 1.03 | Ambiguous | 0.37 | Likely Benign | -6.55 | Deleterious | 0.995 | Probably Damaging | 0.983 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1338G>C | E446D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E446D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a damaging effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Taken together, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -5.668 | Likely Benign | 0.562 | Ambiguous | Likely Benign | 0.171 | Likely Benign | 0.1657 | 0.4275 | 1.65 | Ambiguous | 0.7 | 0.80 | Ambiguous | 1.23 | Ambiguous | 0.68 | Ambiguous | -2.40 | Neutral | 0.986 | Probably Damaging | 0.960 | Probably Damaging | 3.30 | Benign | 0.18 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1338G>T | E446D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E446D lies in the GAP domain. ClinVar has no entry for this variant and it is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools report a pathogenic signal: polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The remaining predictors (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also benign, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Taken together, the majority of evidence points to a benign effect. Thus, the variant is most likely benign, and this is consistent with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | -5.668 | Likely Benign | 0.562 | Ambiguous | Likely Benign | 0.171 | Likely Benign | 0.1657 | 0.4275 | 1.65 | Ambiguous | 0.7 | 0.80 | Ambiguous | 1.23 | Ambiguous | 0.68 | Ambiguous | -2.40 | Neutral | 0.986 | Probably Damaging | 0.960 | Probably Damaging | 3.30 | Benign | 0.18 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1339G>A | V447I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Thus, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -5.067 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.0625 | 0.3059 | -0.33 | Likely Benign | 0.1 | 0.27 | Likely Benign | -0.03 | Likely Benign | -0.44 | Likely Benign | -0.06 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.37 | Benign | 0.28 | Tolerated | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||
| c.1339G>C | V447L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results are reported by FoldX, Rosetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -5.136 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.180 | Likely Benign | 0.0757 | 0.3477 | -1.13 | Ambiguous | 0.1 | 0.54 | Ambiguous | -0.30 | Likely Benign | 0.03 | Likely Benign | -0.29 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.61 | Benign | 0.90 | Tolerated | 3.37 | 32 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||
| c.1339G>T | V447F 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V447F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain effect on protein folding. Overall, the majority of predictions lean toward pathogenicity, suggesting the variant is most likely pathogenic, a conclusion that does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -8.673 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.206 | Likely Benign | 0.0551 | 0.3055 | 1.40 | Ambiguous | 0.3 | 0.61 | Ambiguous | 1.01 | Ambiguous | 0.20 | Likely Benign | -2.62 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||
| c.1340T>A | V447D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V447D lies in the GAP domain. ClinVar has no entry for this change, and it is absent from gnomAD. Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining predictors—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify the variant as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta also reports a pathogenic effect. Overall, the evidence points to a pathogenic effect for V447D, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -16.643 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.491 | Likely Benign | 0.1424 | 0.0541 | 4.34 | Destabilizing | 0.1 | 3.59 | Destabilizing | 3.97 | Destabilizing | 2.29 | Destabilizing | -5.33 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| c.1340T>C | V447A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V447A missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenicity. No predictions are missing or inconclusive. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -9.852 | Likely Pathogenic | 0.692 | Likely Pathogenic | Likely Benign | 0.266 | Likely Benign | 0.2456 | 0.2124 | 2.18 | Destabilizing | 0.0 | 2.72 | Destabilizing | 2.45 | Destabilizing | 1.56 | Destabilizing | -2.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.15 | Tolerated | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| c.1340T>G | V447G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V447G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM, while the remaining tools—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that V447G is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -13.648 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.499 | Likely Benign | 0.1863 | 0.2240 | 3.81 | Destabilizing | 0.1 | 4.62 | Destabilizing | 4.22 | Destabilizing | 2.28 | Destabilizing | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1342G>A | A448T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A448T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain and therefore not counted. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming majority of evidence indicates that A448T is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.192 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.558 | Likely Pathogenic | 0.1187 | 0.5050 | 3.06 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.73 | Destabilizing | 0.63 | Ambiguous | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1342G>C | A448P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely pathogenic result; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -13.706 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.650 | Likely Pathogenic | 0.1758 | 0.3626 | 5.42 | Destabilizing | 0.0 | 8.74 | Destabilizing | 7.08 | Destabilizing | 1.16 | Destabilizing | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1342G>T | A448S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A448S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.213 | Likely Pathogenic | 0.590 | Likely Pathogenic | Likely Benign | 0.310 | Likely Benign | 0.2420 | 0.3471 | 1.18 | Ambiguous | 0.1 | 1.97 | Ambiguous | 1.58 | Ambiguous | 0.55 | Ambiguous | -2.96 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.27 | Benign | 0.06 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1343C>A | A448D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448D is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -17.290 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.662 | Likely Pathogenic | 0.1541 | 0.1741 | 8.13 | Destabilizing | 0.2 | 4.35 | Destabilizing | 6.24 | Destabilizing | 1.40 | Destabilizing | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.1343C>G | A448G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448G resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; FoldX is inconclusive. High‑accuracy assessments further clarify the impact: AlphaMissense‑Optimized reports a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -9.984 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 0.378 | Likely Benign | 0.2135 | 0.2936 | 1.76 | Ambiguous | 0.0 | 2.45 | Destabilizing | 2.11 | Destabilizing | 1.00 | Destabilizing | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.15 | Benign | 0.06 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1343C>T | A448V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools (Rosetta and premPS) yield uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates that A448V is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -10.372 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.487 | Likely Benign | 0.0950 | 0.4955 | 3.31 | Destabilizing | 0.2 | 1.80 | Ambiguous | 2.56 | Destabilizing | 0.66 | Ambiguous | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.26 | Benign | 0.02 | Affected | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1345A>C | S449R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S449R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifying it as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain stability change. No folding‑stability prediction is definitive. Overall, the majority of tools predict a benign outcome, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.145 | Likely Benign | 0.0762 | 0.3250 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1345A>G | S449G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449G is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (variant ID 6‑33438250‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as “Likely Benign,” and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | Uncertain | 1 | 6-33438250-A-G | 3 | 1.86e-6 | -5.936 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.2600 | 0.3718 | 0.47 | Likely Benign | 0.0 | 0.55 | Ambiguous | 0.51 | Ambiguous | 0.85 | Ambiguous | -2.32 | Neutral | 0.948 | Possibly Damaging | 0.124 | Benign | 3.35 | Benign | 0.13 | Tolerated | 3.37 | 32 | 0 | 1 | 0.4 | -30.03 | ||||||||||||||||||
| c.1345A>T | S449C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449C is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Based on the unanimous benign predictions and lack of ClinVar evidence, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -2.207 | Likely Benign | 0.050 | Likely Benign | Likely Benign | 0.067 | Likely Benign | 0.0864 | 0.5012 | 0.48 | Likely Benign | 0.0 | -0.31 | Likely Benign | 0.09 | Likely Benign | -0.57 | Ambiguous | 0.48 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.32 | Benign | 0.21 | Tolerated | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.1346G>A | S449N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449N is not reported in ClinVar (ClinVar status: not listed) but is present in the gnomAD database (gnomAD ID: 6‑33438251‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS (uncertain) and ESM1b (uncertain). High‑accuracy assessments reinforce the benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | 6-33438251-G-A | 1 | 6.19e-7 | -7.692 | In-Between | 0.210 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.1085 | 0.3767 | 0.38 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.18 | Likely Benign | 0.81 | Ambiguous | -2.31 | Neutral | 0.372 | Benign | 0.026 | Benign | 3.37 | Benign | 0.18 | Tolerated | 3.37 | 32 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||
| c.1346G>C | S449T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on these predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -6.262 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.1219 | 0.5077 | 0.36 | Likely Benign | 0.1 | -0.46 | Likely Benign | -0.05 | Likely Benign | -0.15 | Likely Benign | -1.48 | Neutral | 0.038 | Benign | 0.008 | Benign | 3.42 | Benign | 0.33 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1346G>T | S449I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic). Foldetta also remains uncertain. Overall, the majority of evidence (7 benign vs. 3 pathogenic) points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -9.549 | Likely Pathogenic | 0.310 | Likely Benign | Likely Benign | 0.105 | Likely Benign | 0.0756 | 0.5006 | 0.04 | Likely Benign | 0.1 | -1.39 | Ambiguous | -0.68 | Ambiguous | 0.13 | Likely Benign | -3.23 | Deleterious | 0.559 | Possibly Damaging | 0.044 | Benign | 3.40 | Benign | 0.14 | Tolerated | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||
| c.1347T>A | S449R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments provide a mixed picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. FoldX and Rosetta predictions are also uncertain and are treated as unavailable. Overall, the evidence is balanced, with an equal number of benign and pathogenic calls, and the high‑accuracy tools do not converge on a single conclusion. Consequently, the variant is most likely pathogenic based on the preponderance of pathogenic predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.168 | Likely Benign | 0.0762 | 0.3250 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1347T>G | S449R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449R is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that classify the variant as benign include REVEL, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicting a benign effect, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta’s stability prediction is uncertain and therefore treated as unavailable. Overall, the predictions are split, with an equal number of benign and pathogenic calls and conflicting high‑accuracy results. Consequently, the variant’s impact remains inconclusive, and there is no contradiction with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -8.486 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.167 | Likely Benign | 0.0762 | 0.3250 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1348G>A | A450T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Because the majority of conventional tools lean toward benign and no ClinVar evidence contradicts this, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -9.149 | Likely Pathogenic | 0.380 | Ambiguous | Likely Benign | 0.233 | Likely Benign | 0.0943 | 0.5902 | 0.50 | Ambiguous | 0.2 | 0.98 | Ambiguous | 0.74 | Ambiguous | 0.81 | Ambiguous | -3.35 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.06 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| c.1348G>C | A450P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450P missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score all classify the change as pathogenic. The high‑accuracy predictors give consistent pathogenic results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. premPS remains uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which is consistent with the absence of a benign ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -15.378 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.459 | Likely Benign | 0.1494 | 0.4309 | 2.75 | Destabilizing | 0.3 | 8.32 | Destabilizing | 5.54 | Destabilizing | 0.72 | Ambiguous | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1348G>T | A450S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A450S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining methods—FoldX, Rosetta, Foldetta, and premPS—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus unavailable; Foldetta is uncertain. Overall, the balance of evidence (five benign versus four pathogenic predictions, with three uncertain) suggests the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -9.257 | Likely Pathogenic | 0.274 | Likely Benign | Likely Benign | 0.268 | Likely Benign | 0.2003 | 0.4322 | 0.81 | Ambiguous | 0.0 | 1.35 | Ambiguous | 1.08 | Ambiguous | 0.69 | Ambiguous | -2.70 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||
| c.1349C>A | A450E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A450E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include SIFT and FATHMM, whereas the majority of tools predict it to be pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No predictions are inconclusive. Overall, the evidence strongly favors a pathogenic impact for A450E, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | Uncertain | 1 | -16.578 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.653 | Likely Pathogenic | 0.0823 | 0.1695 | 3.86 | Destabilizing | 0.2 | 5.23 | Destabilizing | 4.55 | Destabilizing | 1.59 | Destabilizing | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.38 | Benign | 0.07 | Tolerated | 3.37 | 32 | 0 | -1 | -5.3 | 58.04 | 240.1 | -82.6 | 0.0 | 0.0 | 0.7 | 0.0 | X | X | Potentially Pathogenic | The methyl group of Ala450, located in an α helix (res. Asn440-Thr458), packs against hydrophobic residues in the inter-helix space (e.g., Leu692). In the variant simulations, the carboxylate group of the Glu450 side chain rotates outward, away from the hydrophobic niche, where it does not form any lasting salt bridges or H-bonds. Although the residue swap does not negatively affect the protein structure based on the simulations, it is possible that the introduction of the negatively charged residue adversely affects the folding process or tertiary assembly. | |||||||||||
| c.1349C>G | A450G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A450G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. The majority of other in silico predictors (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) classify the variant as pathogenic; FoldX is inconclusive. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenic. Overall, the preponderance of evidence indicates that A450G is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | -11.090 | Likely Pathogenic | 0.695 | Likely Pathogenic | Likely Benign | 0.355 | Likely Benign | 0.1670 | 0.3078 | 1.79 | Ambiguous | 0.0 | 2.29 | Destabilizing | 2.04 | Destabilizing | 1.23 | Destabilizing | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1349C>T | A450V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A450V is not reported in ClinVar and is present in gnomAD (ID 6‑33438254‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of tools lean toward a benign effect, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign based on current predictions, with a single high‑accuracy tool suggesting pathogenicity but not overturning the overall benign consensus. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.321458 | Structured | 0.306281 | Uncertain | 0.963 | 0.234 | 0.000 | 6-33438254-C-T | 1 | 6.20e-7 | -11.489 | Likely Pathogenic | 0.578 | Likely Pathogenic | Likely Benign | 0.306 | Likely Benign | 0.0792 | 0.5638 | 0.04 | Likely Benign | 0.2 | 0.27 | Likely Benign | 0.16 | Likely Benign | 0.46 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.55 | Benign | 0.04 | Affected | 3.37 | 32 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||
| c.1351C>A | L451I 2D AIThe SynGAP1 L451I missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results come from FoldX, Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, the majority of available predictions (five pathogenic versus four benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -11.046 | Likely Pathogenic | 0.658 | Likely Pathogenic | Likely Benign | 0.284 | Likely Benign | 0.0681 | 0.2958 | 1.43 | Ambiguous | 0.8 | 0.70 | Ambiguous | 1.07 | Ambiguous | 0.94 | Ambiguous | -1.94 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.75 | Benign | 0.02 | Affected | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1351C>G | L451V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451V is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain and does not contribute to the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; and Foldetta predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for L451V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -10.732 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 0.325 | Likely Benign | 0.1065 | 0.2856 | 2.83 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.32 | Destabilizing | 1.39 | Destabilizing | -2.90 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1352T>A | L451Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451Q is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -15.426 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.708 | Likely Pathogenic | 0.0869 | 0.0558 | 2.91 | Destabilizing | 0.0 | 2.48 | Destabilizing | 2.70 | Destabilizing | 2.30 | Destabilizing | -5.79 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1352T>C | L451P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451P is reported in ClinVar as Pathogenic (ClinVar ID 3064222.0) and is not found in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on these predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | Likely Pathogenic | 1 | -14.549 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.750 | Likely Pathogenic | 0.2823 | 0.1221 | 6.92 | Destabilizing | 0.2 | 8.57 | Destabilizing | 7.75 | Destabilizing | 2.58 | Destabilizing | -6.81 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 3.37 | 34 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||
| c.1352T>G | L451R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in‑silico predictors classify the substitution as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a pathogenic effect. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -16.162 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.726 | Likely Pathogenic | 0.1130 | 0.0558 | 3.32 | Destabilizing | 0.1 | 3.76 | Destabilizing | 3.54 | Destabilizing | 2.25 | Destabilizing | -5.82 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1354G>A | V452I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, while ESM1b also predicts pathogenicity. Uncertain predictions come from Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar “Uncertain” classification, which remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 1 | -8.985 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.218 | Likely Benign | 0.0630 | 0.3476 | -0.08 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.22 | Likely Benign | 0.25 | Likely Benign | -0.99 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.26 | Benign | 0.05 | Affected | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||
| c.1354G>C | V452L 2D 3DClick to see structure in 3D Viewer AISynGAP1 V452L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Because the majority of tools (six) predict benign and the high‑accuracy Foldetta also supports benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -11.285 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 0.316 | Likely Benign | 0.0777 | 0.4061 | 0.29 | Likely Benign | 0.1 | -0.25 | Likely Benign | 0.02 | Likely Benign | 0.34 | Likely Benign | -2.96 | Deleterious | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.54 | Benign | 0.11 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1354G>T | V452F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V452F variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools (REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that contradicts its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 1 | -14.769 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.511 | Likely Pathogenic | 0.0564 | 0.3451 | 9.21 | Destabilizing | 0.1 | 0.37 | Likely Benign | 4.79 | Destabilizing | 0.61 | Ambiguous | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 3.37 | 34 | -1 | -1 | -1.4 | 48.04 | 249.4 | -35.7 | 0.0 | 0.0 | 0.4 | 0.1 | X | Potentially Pathogenic | The iso-propyl side chain of Val452, located in the middle of an α helix (res. Val441-Ser457), packs against hydrophobic residues in the inter-helix space at the intersection of three α helices (e.g., Leu500, His453, Leu465). In the variant simulations, the larger side chain of Phe452 cannot pack against the opposing α helix (res. Leu489-Glu519) as efficiently as valine. Due to space restrictions, the phenol ring adjusts to make room by rotating slightly sideways in the inter-helix space. Besides this small and local shift, no large-scale effects on the protein structure are seen based on the simulations. However, the size difference between the swapped residues could affect the protein folding process. | ||||||||||||
| c.1355T>A | V452D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -15.793 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.630 | Likely Pathogenic | 0.1320 | 0.0610 | 3.92 | Destabilizing | 0.1 | 3.37 | Destabilizing | 3.65 | Destabilizing | 2.52 | Destabilizing | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.00 | Affected | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||
| c.1355T>C | V452A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V452A is not reported in ClinVar and has no entry in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available tools points to a pathogenic effect for V452A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -10.423 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.505 | Likely Pathogenic | 0.2642 | 0.2521 | 2.21 | Destabilizing | 0.0 | 1.51 | Ambiguous | 1.86 | Ambiguous | 2.18 | Destabilizing | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.21 | Benign | 0.00 | Affected | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| c.1355T>G | V452G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V452G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, providing no definitive direction. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. AlphaMissense‑Optimized remains uncertain. Overall, the preponderance of evidence indicates that V452G is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -13.410 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.570 | Likely Pathogenic | 0.1948 | 0.2567 | 3.70 | Destabilizing | 0.1 | 3.37 | Destabilizing | 3.54 | Destabilizing | 2.46 | Destabilizing | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1357C>A | H453N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H453N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. A third set of methods (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yield uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the majority of evidence points toward a pathogenic effect for H453N. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -8.416 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 0.347 | Likely Benign | 0.1435 | 0.2548 | 0.93 | Ambiguous | 0.1 | 0.97 | Ambiguous | 0.95 | Ambiguous | 0.78 | Ambiguous | -6.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||
| c.1357C>G | H453D 2D 3DClick to see structure in 3D Viewer AISynGAP1 H453D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods reinforce a pathogenic interpretation: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenicity. premPS remains uncertain. Overall, the majority of evidence points to a pathogenic effect for H453D, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.256 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.443 | Likely Benign | 0.2225 | 0.1815 | 3.33 | Destabilizing | 0.0 | 2.68 | Destabilizing | 3.01 | Destabilizing | 0.97 | Ambiguous | -8.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||
| c.1357C>T | H453Y 2D AIThe SynGAP1 missense variant H453Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Predictions from FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy methods provide a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts likely pathogenic, and Foldetta is inconclusive. Overall, the majority of evidence points toward a pathogenic effect, aligning with the SGM‑Consensus but opposing the benign predictions from several tools. Because ClinVar contains no entry for this variant, there is no conflict with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -12.060 | Likely Pathogenic | 0.753 | Likely Pathogenic | Likely Benign | 0.320 | Likely Benign | 0.0815 | 0.3843 | -0.52 | Ambiguous | 0.7 | -0.68 | Ambiguous | -0.60 | Ambiguous | 0.09 | Likely Benign | -5.93 | Deleterious | 0.995 | Probably Damaging | 0.961 | Probably Damaging | 3.41 | Benign | 0.04 | Affected | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||
| c.1358A>C | H453P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H453P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM. The majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.704 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.488 | Likely Benign | 0.2115 | 0.3938 | 3.29 | Destabilizing | 0.4 | 7.04 | Destabilizing | 5.17 | Destabilizing | 0.84 | Ambiguous | -9.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||
| c.1358A>G | H453R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H453R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an inconclusive result because FoldX is uncertain and Rosetta is benign. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -9.239 | Likely Pathogenic | 0.573 | Likely Pathogenic | Likely Benign | 0.396 | Likely Benign | 0.1646 | 0.2031 | -0.52 | Ambiguous | 0.1 | 0.37 | Likely Benign | -0.08 | Likely Benign | 0.56 | Ambiguous | -7.91 | Deleterious | 0.993 | Probably Damaging | 0.957 | Probably Damaging | 3.53 | Benign | 0.39 | Tolerated | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||
| c.1358A>T | H453L 2D 3DClick to see structure in 3D Viewer AISynGAP1 H453L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, premPS, SIFT, FATHMM, and the protein‑folding stability method Foldetta; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments indicate that AlphaMissense‑Optimized is uncertain, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the predictions are split, with a slight edge toward pathogenicity from the consensus and high‑accuracy tools, but the presence of several benign calls and the uncertainty of AlphaMissense‑Optimized temper this conclusion. Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -10.438 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.413 | Likely Benign | 0.0841 | 0.4964 | -0.59 | Ambiguous | 0.1 | 0.04 | Likely Benign | -0.28 | Likely Benign | 0.31 | Likely Benign | -10.87 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.45 | Benign | 0.11 | Tolerated | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||
| c.1359C>A | H453Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H453Q is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, Rosetta, premPS, AlphaMissense‑Optimized, and Foldetta—are treated as unavailable for pathogenicity assessment. High‑accuracy methods specifically show SGM‑Consensus as Likely Pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the preponderance of evidence from consensus and high‑accuracy predictors indicates that H453Q is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -10.894 | Likely Pathogenic | 0.893 | Likely Pathogenic | Ambiguous | 0.259 | Likely Benign | 0.1223 | 0.3112 | 0.90 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.23 | Ambiguous | 0.92 | Ambiguous | -7.91 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.09 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1359C>G | H453Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H453Q is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized—are treated as unavailable for pathogenicity assessment. High‑accuracy methods specifically show SGM‑Consensus as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for H453Q. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -10.894 | Likely Pathogenic | 0.893 | Likely Pathogenic | Ambiguous | 0.258 | Likely Benign | 0.1223 | 0.3112 | 0.90 | Ambiguous | 0.1 | 1.55 | Ambiguous | 1.23 | Ambiguous | 0.92 | Ambiguous | -7.91 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.09 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1360A>C | I454L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The remaining tools—FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta also uncertain. Overall, the majority of reliable predictors and the SGM Consensus favor a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -7.852 | In-Between | 0.786 | Likely Pathogenic | Ambiguous | 0.246 | Likely Benign | 0.0653 | 0.2857 | 0.57 | Ambiguous | 0.1 | 1.36 | Ambiguous | 0.97 | Ambiguous | 0.80 | Ambiguous | -1.98 | Neutral | 0.908 | Possibly Damaging | 0.943 | Probably Damaging | 3.51 | Benign | 0.26 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1360A>G | I454V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as likely benign, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -4.719 | Likely Benign | 0.657 | Likely Pathogenic | Likely Benign | 0.132 | Likely Benign | 0.0833 | 0.2959 | 1.47 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.42 | Ambiguous | 0.69 | Ambiguous | -0.79 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.40 | Benign | 0.18 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.1360A>T | I454F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. premPS is uncertain and does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -12.468 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.464 | Likely Benign | 0.0422 | 0.2560 | 4.15 | Destabilizing | 0.7 | 2.96 | Destabilizing | 3.56 | Destabilizing | 0.70 | Ambiguous | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.1361T>A | I454N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454N resides in the GAP domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. High‑accuracy methods further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta predicts a destabilizing, pathogenic change. Overall, the evidence strongly favors a pathogenic classification, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -14.246 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.497 | Likely Benign | 0.0750 | 0.0412 | 4.24 | Destabilizing | 0.1 | 3.56 | Destabilizing | 3.90 | Destabilizing | 2.44 | Destabilizing | -6.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.1361T>C | I454T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -9.045 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.502 | Likely Pathogenic | 0.0877 | 0.0708 | 3.20 | Destabilizing | 0.0 | 2.83 | Destabilizing | 3.02 | Destabilizing | 2.02 | Destabilizing | -4.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.1361T>G | I454S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -13.025 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.574 | Likely Pathogenic | 0.2116 | 0.0800 | 4.50 | Destabilizing | 0.1 | 4.45 | Destabilizing | 4.48 | Destabilizing | 2.20 | Destabilizing | -5.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.1362C>G | I454M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools (SGM‑Consensus, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive results are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for I454M. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -8.437 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 0.292 | Likely Benign | 0.0566 | 0.2524 | 1.06 | Ambiguous | 0.1 | 2.32 | Destabilizing | 1.69 | Ambiguous | 1.08 | Destabilizing | -2.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||
| c.1363C>A | L455M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L455M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. No folding‑stability method provides a definitive result. Consequently, the computational evidence does not favor either benign or pathogenic classification. The variant’s status is therefore inconclusive, and this lack of consensus does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -10.086 | Likely Pathogenic | 0.802 | Likely Pathogenic | Ambiguous | 0.147 | Likely Benign | 0.0606 | 0.3362 | 0.88 | Ambiguous | 0.0 | 1.27 | Ambiguous | 1.08 | Ambiguous | 0.59 | Ambiguous | -1.64 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.11 | Tolerated | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.1363C>G | L455V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas the remaining 11 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -12.773 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.276 | Likely Benign | 0.1149 | 0.3056 | 2.89 | Destabilizing | 0.1 | 2.38 | Destabilizing | 2.64 | Destabilizing | 1.41 | Destabilizing | -2.83 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.29 | Benign | 0.02 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1364T>A | L455Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455Q is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -13.075 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.655 | Likely Pathogenic | 0.0871 | 0.0958 | 2.84 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.13 | Destabilizing | 2.24 | Destabilizing | -5.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1364T>C | L455P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -14.150 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.695 | Likely Pathogenic | 0.3211 | 0.1221 | 7.45 | Destabilizing | 0.2 | 11.99 | Destabilizing | 9.72 | Destabilizing | 2.19 | Destabilizing | -6.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1364T>G | L455R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455R resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -16.347 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.648 | Likely Pathogenic | 0.1126 | 0.0600 | 6.36 | Destabilizing | 0.2 | 4.96 | Destabilizing | 5.66 | Destabilizing | 2.08 | Destabilizing | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1366C>A | Q456K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456K is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; premPS and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of tools (six pathogenic vs five benign) and the SGM‑Consensus result point toward a pathogenic interpretation, while Foldetta suggests stability‑preserving benignity. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -13.768 | Likely Pathogenic | 0.806 | Likely Pathogenic | Ambiguous | 0.391 | Likely Benign | 0.1321 | 0.2547 | 0.21 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.22 | Likely Benign | 0.78 | Ambiguous | -3.75 | Deleterious | 0.969 | Probably Damaging | 0.875 | Possibly Damaging | 3.36 | Benign | 0.13 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||
| c.1366C>G | Q456E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remaining uncertain. Overall, the predictions are split, but the high‑accuracy consensus leans toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -12.982 | Likely Pathogenic | 0.503 | Ambiguous | Likely Benign | 0.233 | Likely Benign | 0.1191 | 0.1276 | 0.71 | Ambiguous | 0.1 | 0.87 | Ambiguous | 0.79 | Ambiguous | 0.65 | Ambiguous | -2.76 | Deleterious | 0.998 | Probably Damaging | 0.964 | Probably Damaging | 3.41 | Benign | 0.15 | Tolerated | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.1367A>C | Q456P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q456P is listed in ClinVar with an uncertain significance (ClinVar ID 2697090.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. High‑accuracy methods specifically report pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | Uncertain | 1 | -15.250 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.469 | Likely Benign | 0.2256 | 0.3631 | 3.68 | Destabilizing | 0.2 | 8.43 | Destabilizing | 6.06 | Destabilizing | 0.82 | Ambiguous | -5.66 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.07 | Tolerated | 3.37 | 34 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||
| c.1367A>G | Q456R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta (a folding‑stability method combining FoldX‑MD and Rosetta outputs) predicts benign. No evidence from the data contradicts ClinVar status, which is currently unclassified. Based on the available predictions, the variant is most likely benign, though the evidence is conflicting and does not conflict with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -11.326 | Likely Pathogenic | 0.801 | Likely Pathogenic | Ambiguous | 0.295 | Likely Benign | 0.1241 | 0.1124 | 0.21 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.17 | Likely Benign | 0.33 | Likely Benign | -3.69 | Deleterious | 0.980 | Probably Damaging | 0.943 | Probably Damaging | 3.37 | Benign | 0.20 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||
| c.1367A>T | Q456L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation, with no evidence of contradiction with the ClinVar status. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -10.272 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | 0.347 | Likely Benign | 0.0554 | 0.4317 | -0.88 | Ambiguous | 0.1 | -0.30 | Likely Benign | -0.59 | Ambiguous | 0.28 | Likely Benign | -6.65 | Deleterious | 0.987 | Probably Damaging | 0.914 | Probably Damaging | 3.49 | Benign | 0.36 | Tolerated | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||
| c.1368G>C | Q456H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely benign, though a high‑accuracy consensus suggests a possible pathogenic effect that warrants further investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -7.993 | In-Between | 0.598 | Likely Pathogenic | Likely Benign | 0.214 | Likely Benign | 0.0987 | 0.2358 | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||
| c.1368G>T | Q456H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q456H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions lean toward a benign impact, and this does not contradict the lack of ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely benign, though a high‑accuracy consensus suggests a possible pathogenic effect that warrants further investigation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.170161 | Structured | 0.302348 | Uncertain | 0.939 | 0.164 | 0.000 | -7.993 | In-Between | 0.598 | Likely Pathogenic | Likely Benign | 0.214 | Likely Benign | 0.0987 | 0.2358 | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||
| c.1369A>C | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenic, whereas Foldetta’s stability analysis is uncertain. Overall, the majority of evidence points toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.468 | Likely Benign | 0.0781 | 0.3426 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1369A>G | S457G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S457G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S457G. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -9.154 | Likely Pathogenic | 0.811 | Likely Pathogenic | Ambiguous | 0.382 | Likely Benign | 0.2735 | 0.4074 | 0.86 | Ambiguous | 0.0 | 0.87 | Ambiguous | 0.87 | Ambiguous | 0.65 | Ambiguous | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.35 | Benign | 0.13 | Tolerated | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||
| c.1369A>T | S457C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S457C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give mixed results: AlphaMissense‑Optimized is inconclusive and therefore not used as evidence; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, while the high‑accuracy Foldetta result suggests benign stability. Given the predominance of pathogenic calls and the lack of ClinVar evidence, the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -8.152 | Likely Pathogenic | 0.815 | Likely Pathogenic | Ambiguous | 0.497 | Likely Benign | 0.0865 | 0.6284 | -0.12 | Likely Benign | 0.0 | -0.79 | Ambiguous | -0.46 | Likely Benign | 0.56 | Ambiguous | -4.81 | Deleterious | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.1370G>A | S457N 2D AIThe SynGAP1 missense variant S457N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus methods give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of individual predictors lean toward pathogenicity, but the high‑accuracy Foldetta result suggests a benign impact. Thus, the variant is most likely pathogenic based on the preponderance of predictions, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | Uncertain | 1 | -10.221 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | 0.1015 | 0.4980 | 0.19 | Likely Benign | 0.0 | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.67 | Ambiguous | -2.76 | Deleterious | 0.940 | Possibly Damaging | 0.843 | Possibly Damaging | 3.28 | Benign | 0.06 | Tolerated | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||
| c.1370G>C | S457T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457T has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicting likely pathogenic, and Foldetta predicting benign. Overall, the majority of high‑confidence tools lean toward a benign effect, and there is no conflict with the ClinVar status, which is currently unreported. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -8.772 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.273 | Likely Benign | 0.1154 | 0.6487 | 0.82 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.13 | Likely Benign | 0.38 | Likely Benign | -2.83 | Deleterious | 0.866 | Possibly Damaging | 0.780 | Possibly Damaging | 3.34 | Benign | 0.09 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1370G>T | S457I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457I lies within the GAP domain. ClinVar has no entry for this change, and it is absent from gnomAD. Prediction tools that report a benign effect include FoldX and FATHMM, whereas the majority of other in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized—classify it as pathogenic. Uncertain results come from Rosetta, Foldetta and premPS. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -13.170 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.557 | Likely Pathogenic | 0.0779 | 0.6095 | -0.26 | Likely Benign | 0.3 | -0.96 | Ambiguous | -0.61 | Ambiguous | 0.65 | Ambiguous | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.34 | Benign | 0.02 | Affected | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||
| c.1371T>A | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, SGM‑Consensus confirms a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence from multiple independent predictors indicates that S457R is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.343 | Likely Benign | 0.0781 | 0.3426 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1371T>G | S457R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, SGM‑Consensus confirms a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence from multiple independent predictors indicates that S457R is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -10.882 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.343 | Likely Benign | 0.0781 | 0.3426 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||
| c.1372A>C | T458P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T458P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b, and the SGM‑Consensus) all predict a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a pathogenic effect. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -13.547 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.557 | Likely Pathogenic | 0.2098 | 0.5395 | 3.05 | Destabilizing | 0.2 | 5.36 | Destabilizing | 4.21 | Destabilizing | 0.78 | Ambiguous | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.06 | Tolerated | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||
| c.1372A>G | T458A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of reliable predictors (six pathogenic vs. five benign) indicate a pathogenic effect. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -10.734 | Likely Pathogenic | 0.924 | Likely Pathogenic | Ambiguous | 0.358 | Likely Benign | 0.4137 | 0.4257 | 0.36 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.34 | Likely Benign | 0.56 | Ambiguous | -4.27 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.40 | Benign | 0.15 | Tolerated | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||
| c.1372A>T | T458S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458S missense variant has no ClinVar entry and is not present in gnomAD. Functional prediction tools cluster into two groups: benign calls from REVEL, FoldX, Rosetta, SIFT, and FATHMM; pathogenic calls from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments further split the signal: AlphaMissense‑Optimized remains uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Because the majority of standard predictors are evenly divided and the high‑accuracy methods disagree, the variant’s effect cannot be confidently classified as benign or pathogenic. Thus, the variant is of uncertain significance, and this uncertainty does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -8.465 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | 0.260 | Likely Benign | 0.3525 | 0.4349 | 0.44 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.40 | Likely Benign | 0.55 | Ambiguous | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.48 | Benign | 0.13 | Tolerated | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||
| c.1373C>A | T458K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T458K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting pathogenicity, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicting pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting benign stability. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -13.734 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.373 | Likely Benign | 0.1153 | 0.3326 | -0.59 | Ambiguous | 0.1 | -0.26 | Likely Benign | -0.43 | Likely Benign | 0.80 | Ambiguous | -5.23 | Deleterious | 0.999 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.14 | Tolerated | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||
| c.1373C>G | T458R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T458R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, SIFT, and FATHMM, whereas a larger set—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. Uncertain results come from FoldX and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -12.984 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.390 | Likely Benign | 0.1016 | 0.3013 | -0.81 | Ambiguous | 0.1 | -0.11 | Likely Benign | -0.46 | Likely Benign | 0.61 | Ambiguous | -5.26 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.52 | Benign | 0.20 | Tolerated | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||
| c.1373C>T | T458I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458I missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (seven versus six) and the two high‑accuracy pathogenic predictions suggest the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -9.436 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.337 | Likely Benign | 0.0724 | 0.6128 | -0.40 | Likely Benign | 0.1 | 0.29 | Likely Benign | -0.06 | Likely Benign | 0.50 | Likely Benign | -4.76 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.09 | Tolerated | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.1387G>A | D463N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D463N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain (Foldetta, AlphaMissense‑Optimized, Rosetta) are treated as unavailable and do not influence the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta is uncertain. Overall, the majority of available predictions lean toward a benign effect, and this conclusion does not contradict any ClinVar status (none reported). Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -11.428 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | 0.217 | Likely Benign | 0.1152 | 0.5531 | 0.10 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.65 | Ambiguous | 0.40 | Likely Benign | -4.37 | Deleterious | 0.880 | Possibly Damaging | 0.430 | Benign | 3.33 | Benign | 0.10 | Tolerated | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1387G>C | D463H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant D463H is not reported in ClinVar and is absent from gnomAD. Consensus from standard prediction algorithms shows a split: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, SGM Consensus confirms Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. No evidence from ClinVar contradicts these findings. Overall, the preponderance of computational evidence indicates that D463H is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -13.151 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.356 | Likely Benign | 0.1341 | 0.6156 | 0.20 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.53 | Ambiguous | 0.57 | Ambiguous | -5.96 | Deleterious | 0.996 | Probably Damaging | 0.852 | Possibly Damaging | 3.35 | Benign | 0.11 | Tolerated | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.1387G>T | D463Y 2D  3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 D463Y variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of conventional tools lean toward pathogenicity, while the high‑accuracy Foldetta suggests benign. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -14.387 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.399 | Likely Benign | 0.0540 | 0.6213 | -0.14 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.32 | Likely Benign | 0.07 | Likely Benign | -7.95 | Deleterious | 0.998 | Probably Damaging | 0.904 | Possibly Damaging | 3.35 | Benign | 0.14 | Tolerated | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.1388A>C | D463A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D463A missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, premPS, SIFT, FATHMM, and the folding‑stability method Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely pathogenic, and Foldetta predicts a benign effect on protein stability. Overall, the majority of tools and the consensus high‑accuracy prediction lean toward pathogenicity, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -8.607 | Likely Pathogenic | 0.894 | Likely Pathogenic | Ambiguous | 0.425 | Likely Benign | 0.3591 | 0.5169 | -0.04 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.46 | Likely Benign | 0.43 | Likely Benign | -6.96 | Deleterious | 0.978 | Probably Damaging | 0.602 | Possibly Damaging | 3.33 | Benign | 0.29 | Tolerated | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.1388A>G | D463G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D463G missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools favor pathogenicity versus three favor benign, with the remaining five (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yielding uncertain results. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -10.713 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.422 | Likely Benign | 0.3751 | 0.4898 | 0.66 | Ambiguous | 0.1 | 1.93 | Ambiguous | 1.30 | Ambiguous | 0.54 | Ambiguous | -6.36 | Deleterious | 0.994 | Probably Damaging | 0.824 | Possibly Damaging | 3.32 | Benign | 0.09 | Tolerated | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| c.1388A>T | D463V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D463V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points toward a pathogenic impact for D463V, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -12.374 | Likely Pathogenic | 0.880 | Likely Pathogenic | Ambiguous | 0.521 | Likely Pathogenic | 0.0713 | 0.5526 | 0.23 | Likely Benign | 0.1 | 0.98 | Ambiguous | 0.61 | Ambiguous | 0.33 | Likely Benign | -7.95 | Deleterious | 0.973 | Probably Damaging | 0.658 | Possibly Damaging | 3.31 | Benign | 0.09 | Tolerated | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.1389C>A | D463E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D463E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and premPS. Only PROVEAN predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -5.170 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.162 | Likely Benign | 0.1330 | 0.5177 | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| c.1389C>G | D463E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and premPS. Only PROVEAN predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign, and Foldetta also indicates benign stability. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the collective evidence, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -5.170 | Likely Benign | 0.527 | Ambiguous | Likely Benign | 0.162 | Likely Benign | 0.1330 | 0.5177 | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||
| c.1390T>A | F464I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, while all other evaluated algorithms—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -11.210 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.539 | Likely Pathogenic | 0.1439 | 0.2002 | 4.77 | Destabilizing | 0.2 | 4.35 | Destabilizing | 4.56 | Destabilizing | 1.23 | Destabilizing | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.1390T>C | F464L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability assessments. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s combined FoldX‑MD and Rosetta output is uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.482 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.435 | Likely Benign | 0.1664 | 0.2883 | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1390T>G | F464V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F464V variant is listed in ClinVar with an “Uncertain” status (ClinVar ID 1716596.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective predictions, the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | Uncertain | 1 | -12.254 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.592 | Likely Pathogenic | 0.1587 | 0.2219 | 3.61 | Destabilizing | 0.1 | 2.89 | Destabilizing | 3.25 | Destabilizing | 1.40 | Destabilizing | -6.96 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.36 | Benign | 0.04 | Affected | 3.37 | 34 | -1 | -1 | 1.4 | -48.04 | 210.1 | 40.5 | -0.1 | 0.0 | -0.9 | 0.3 | X | Potentially Pathogenic | The phenyl ring of Phe464, located in the middle of an α helix (res. Ala461–Phe476), packs against hydrophobic residues (e.g., Met468, Leu451, Leu455, and Tyr428) in the inter-helix space formed with two other α helices (res. Asn440-Lys460 and res. Pro413-Glu436). The iso-propyl side chain of Val464 is similarly hydrophobic but considerably smaller than the original phenyl ring of Phe464. To compensate for the size difference, neighboring residues need to fill in the gap in the variant simulations.The phenolic side chain of Tyr428, located at the middle bend of an α helix (res. Glu436-Pro413), assumes a new position in the inter-helix space or rotates inward next to the third α helix (res. Asn440-Lys460) when the stable H-bond between Tyr428 and Asp467 seen in the WT simulations breaks. The residue swap also leads to the loss of the methionine-aromatic interaction between the Met468 and Phe464 side chains, which could weaken the integrity of the parent α helix (res. Ala461-Phe476). Although the simulations likely underestimate the full adverse effect of the introduced mutation during folding, the two opposing α helices (res. Ala461–Phe476 and res. Glu436-Pro413) move substantially closer to each other in the variant simulations. | ||||||||||||
| c.1391T>A | F464Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide uncertain results and are treated as unavailable evidence. Overall, the balance of evidence points to a pathogenic effect for F464Y, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.056 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.387 | Likely Benign | 0.1081 | 0.1523 | 1.35 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.80 | Ambiguous | 1.31 | Destabilizing | -2.98 | Deleterious | 0.979 | Probably Damaging | 0.953 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.1391T>C | F464S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -13.361 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.748 | Likely Pathogenic | 0.3700 | 0.0358 | 4.84 | Destabilizing | 0.0 | 4.90 | Destabilizing | 4.87 | Destabilizing | 2.52 | Destabilizing | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.1391T>G | F464C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -13.011 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.740 | Likely Pathogenic | 0.2298 | 0.1219 | 4.18 | Destabilizing | 0.0 | 4.31 | Destabilizing | 4.25 | Destabilizing | 2.20 | Destabilizing | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.1392C>A | F464L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability assessments. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s combined FoldX‑MD and Rosetta output is uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.482 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.279 | Likely Benign | 0.1664 | 0.2883 | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1392C>G | F464L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability assessments. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s combined FoldX‑MD and Rosetta output is uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.482 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.279 | Likely Benign | 0.1664 | 0.2883 | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1393C>A | L465I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L465I missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score classifies the variant as benign, whereas the Foldetta stability assessment is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive due to a 2‑to‑2 split. Overall, the evidence is mixed; the balance of predictions leans toward a benign interpretation, and this does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -9.672 | Likely Pathogenic | 0.770 | Likely Pathogenic | Likely Benign | 0.258 | Likely Benign | 0.0967 | 0.3539 | 1.21 | Ambiguous | 0.1 | 1.27 | Ambiguous | 1.24 | Ambiguous | 0.78 | Ambiguous | -1.99 | Neutral | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 2.54 | Benign | 0.08 | Tolerated | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1393C>G | L465V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while the remaining tools—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default—indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports likely pathogenic; and Foldetta, which combines FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | Uncertain | 1 | -9.893 | Likely Pathogenic | 0.838 | Likely Pathogenic | Ambiguous | 0.276 | Likely Benign | 0.1493 | 0.3378 | 2.46 | Destabilizing | 0.1 | 2.66 | Destabilizing | 2.56 | Destabilizing | 1.21 | Destabilizing | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.44 | Pathogenic | 0.10 | Tolerated | 3.37 | 34 | 2 | 1 | 0.4 | -14.03 | 204.3 | 30.9 | 0.0 | 0.0 | -0.4 | 0.6 | X | Potentially Benign | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the iso-propyl side chain of Val465 is equally sized and similarly hydrophobic as the original side chain of Leu465. Hence, the mutation does not exert any negative effects on the protein structure based on the variant simulations. | ||||||||||||
| c.1393C>T | L465F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465F is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas the majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus also pathogenic, and Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect for L465F. This conclusion is not contradicted by ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -12.626 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.432 | Likely Benign | 0.0771 | 0.2759 | 3.11 | Destabilizing | 0.7 | 0.05 | Likely Benign | 1.58 | Ambiguous | 0.52 | Ambiguous | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1394T>A | L465H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -16.751 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.764 | Likely Pathogenic | 0.1289 | 0.1089 | 3.15 | Destabilizing | 0.4 | 2.29 | Destabilizing | 2.72 | Destabilizing | 2.54 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| c.1394T>C | L465P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465P is listed in ClinVar as Pathogenic (ClinVar ID 1067821.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | Likely Pathogenic | 1 | -14.824 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.778 | Likely Pathogenic | 0.3387 | 0.1582 | 7.18 | Destabilizing | 0.3 | 10.85 | Destabilizing | 9.02 | Destabilizing | 2.73 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 3.37 | 34 | -3 | -3 | -5.4 | -16.04 | 211.1 | 65.9 | 0.1 | 0.0 | -0.2 | 0.0 | X | Potentially Pathogenic | The iso-butyl side chain of Leu465, located in the middle of an α helix (res. Ala461–Phe476), packs with hydrophobic residues (e.g., Phe464, Met468, Tyr497, Ile494) in an inter-helix space formed with two other α helices (res. Ala461–Phe476 and res. Thr488-Gly502). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro465 is not as optimal as the side chain of Leu465 for filling the three α helix hydrophobic niche. Although the residue swap does not cause a large-scale conformational shift during the simulations, the H-bond between the backbone amide group of Leu465 and the backbone carbonyl group of Ala461 is lost. This, in turn, breaks the continuity of the α helix secondary structure element. | ||||||||||||
| c.1394T>G | L465R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No inconclusive or missing results are present. Based on the consensus of all available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -17.976 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.761 | Likely Pathogenic | 0.1597 | 0.0963 | 4.52 | Destabilizing | 0.7 | 4.44 | Destabilizing | 4.48 | Destabilizing | 2.41 | Destabilizing | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1396T>A | S466T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence points to a benign impact. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -5.488 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.414 | Likely Benign | 0.0928 | 0.5152 | 0.30 | Likely Benign | 0.2 | -1.02 | Ambiguous | -0.36 | Likely Benign | -0.65 | Ambiguous | 1.05 | Neutral | 0.740 | Possibly Damaging | 0.872 | Possibly Damaging | -1.51 | Pathogenic | 1.00 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1396T>C | S466P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466P is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS (Uncertain). High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -13.107 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.811 | Likely Pathogenic | 0.1617 | 0.4915 | 2.67 | Destabilizing | 0.2 | 2.83 | Destabilizing | 2.75 | Destabilizing | 0.95 | Ambiguous | -3.02 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | -1.55 | Pathogenic | 0.04 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||
| c.1396T>G | S466A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: pathogenic scores are given by REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas benign predictions come from SIFT, PROVEAN, premPS, ESM1b, Rosetta, Foldetta, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, the SGM‑Consensus itself is Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Benign. FoldX alone is Uncertain, but this does not alter the overall consensus. Taken together, the majority of evidence indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -6.928 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.537 | Likely Pathogenic | 0.4245 | 0.3996 | -0.50 | Ambiguous | 0.1 | 0.06 | Likely Benign | -0.22 | Likely Benign | 0.37 | Likely Benign | -1.46 | Neutral | 0.909 | Possibly Damaging | 0.987 | Probably Damaging | -1.51 | Pathogenic | 0.10 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| c.1397C>T | S466L 2D  AIThe SynGAP1 missense variant S466L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include FoldX, while the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Tools with uncertain or inconclusive results are AlphaMissense‑Optimized, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S466L. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -9.417 | Likely Pathogenic | 0.806 | Likely Pathogenic | Ambiguous | 0.768 | Likely Pathogenic | 0.0666 | 0.4884 | -0.36 | Likely Benign | 1.6 | -1.60 | Ambiguous | -0.98 | Ambiguous | -0.52 | Ambiguous | -3.05 | Deleterious | 0.995 | Probably Damaging | 0.991 | Probably Damaging | -1.56 | Pathogenic | 0.03 | Affected | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||
| c.1399G>A | D467N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D467N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of the four high‑accuracy predictors) all predict a deleterious effect. Benign predictions come from FoldX, premPS, and SIFT. Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy methods specifically give an uncertain result for AlphaMissense‑Optimized, a pathogenic verdict for the SGM‑Consensus, and an uncertain outcome for Foldetta. Overall, the balance of evidence favors a pathogenic impact for D467N, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -11.881 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.673 | Likely Pathogenic | 0.0936 | 0.4879 | 0.43 | Likely Benign | 0.1 | 1.63 | Ambiguous | 1.03 | Ambiguous | 0.38 | Likely Benign | -4.82 | Deleterious | 0.987 | Probably Damaging | 0.990 | Probably Damaging | -1.22 | Pathogenic | 0.06 | Tolerated | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1399G>C | D467H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only premPS, whereas the remaining evaluated algorithms uniformly predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta yield uncertain results and are treated as unavailable. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta remains uncertain. Overall, the variant is most likely pathogenic based on the consensus of the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -13.348 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.851 | Likely Pathogenic | 0.1074 | 0.5564 | 1.05 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.82 | Ambiguous | 0.32 | Likely Benign | -6.71 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.31 | Pathogenic | 0.02 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.1399G>T | D467Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467Y is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Foldetta, premPS, and SIFT, whereas pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No evidence from Rosetta is available due to its uncertain status. Overall, the majority of high‑confidence predictions lean toward pathogenicity, and this does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -14.373 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.846 | Likely Pathogenic | 0.0517 | 0.5521 | 0.36 | Likely Benign | 0.1 | -0.60 | Ambiguous | -0.12 | Likely Benign | 0.07 | Likely Benign | -8.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.28 | Pathogenic | 0.07 | Tolerated | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.1400A>C | D467A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results—FoldX, Rosetta, and Foldetta—do not provide decisive evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.499 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.790 | Likely Pathogenic | 0.3134 | 0.5117 | 0.83 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.81 | Ambiguous | 0.23 | Likely Benign | -7.71 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.19 | Pathogenic | 0.07 | Tolerated | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.1400A>G | D467G 2D AISynGAP1 missense variant D467G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from premPS, while all other evaluated algorithms—including SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -12.973 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.910 | Likely Pathogenic | 0.3455 | 0.4908 | 1.87 | Ambiguous | 0.8 | 2.55 | Destabilizing | 2.21 | Destabilizing | 0.23 | Likely Benign | -6.81 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| c.1400A>T | D467V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467V missense variant is not reported in ClinVar or gnomAD. Prediction tools cluster into two groups: benign predictions come from Rosetta and premPS, while the majority—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. Two tools, FoldX and Foldetta, give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect, and this conclusion is consistent with the absence of any ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -15.041 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.893 | Likely Pathogenic | 0.0644 | 0.5274 | 1.24 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.66 | Ambiguous | 0.02 | Likely Benign | -8.70 | Deleterious | 0.997 | Probably Damaging | 0.997 | Probably Damaging | -1.28 | Pathogenic | 0.02 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.1401C>A | D467E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467E is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33438433‑C‑A). Prediction tools that agree on a benign effect include only FoldX. Tools that agree on a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive predictions come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable predictors indicate a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | 6-33438433-C-A | 2 | 1.24e-6 | -9.774 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.576 | Likely Pathogenic | 0.1061 | 0.4564 | 0.36 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.62 | Ambiguous | 0.60 | Ambiguous | -3.63 | Deleterious | 0.887 | Possibly Damaging | 0.938 | Probably Damaging | -1.08 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||
| c.1401C>G | D467E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467E missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive predictions come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -9.774 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.576 | Likely Pathogenic | 0.1061 | 0.4564 | 0.36 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.62 | Ambiguous | 0.60 | Ambiguous | -3.63 | Deleterious | 0.887 | Possibly Damaging | 0.938 | Probably Damaging | -1.08 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||
| c.1402A>C | M468L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments—all available—show benign predictions: AlphaMissense‑Optimized (Benign), SGM‑Consensus (Likely Benign), and Foldetta (Benign). Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -6.886 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.412 | Likely Benign | 0.1564 | 0.4408 | 0.43 | Likely Benign | 0.1 | -0.38 | Likely Benign | 0.03 | Likely Benign | -0.35 | Likely Benign | 0.19 | Neutral | 0.359 | Benign | 0.654 | Possibly Damaging | -0.73 | Pathogenic | 1.00 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1402A>G | M468V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools, premPS and AlphaMissense‑Default, return uncertain results. High‑accuracy assessments further clarify the variant’s impact: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also classifies the variant as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 1 | -9.461 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | 0.570 | Likely Pathogenic | 0.3309 | 0.3845 | 2.69 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.45 | Destabilizing | 0.89 | Ambiguous | -1.66 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.21 | Pathogenic | 0.08 | Tolerated | 3.37 | 31 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||
| c.1402A>T | M468L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign outcome. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -6.886 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.412 | Likely Benign | 0.1564 | 0.4408 | 0.43 | Likely Benign | 0.1 | -0.38 | Likely Benign | 0.03 | Likely Benign | -0.35 | Likely Benign | 0.19 | Neutral | 0.359 | Benign | 0.654 | Possibly Damaging | -0.73 | Pathogenic | 1.00 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1403T>A | M468K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468K is listed in ClinVar (ID 642691.0) as Pathogenic and is not reported in gnomAD. All available in silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Likely Pathogenic | 1 | -16.982 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.828 | Likely Pathogenic | 0.1576 | 0.0456 | 3.21 | Destabilizing | 0.1 | 3.30 | Destabilizing | 3.26 | Destabilizing | 2.57 | Destabilizing | -4.61 | Deleterious | 0.878 | Possibly Damaging | 0.922 | Probably Damaging | -1.34 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0 | -1 | -5.8 | -3.02 | 188.7 | 69.3 | 0.0 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the positively charged side chain of Lys468 rotates outward to escape the hydrophobic niche, forming an H-bond with the hydroxyl group of the Ser471 side chain and a salt bridge with the carboxylate group of the Glu472 side chain. This residue swap also disrupts the methionine-aromatic stacking with the phenyl ring of the Phe464 side chain. Although no large-scale structural changes are observed during the variant simulations, the importance of hydrophobic packing suggests that the effects could be more pronounced during protein folding. | |||||||||||
| c.1403T>C | M468T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database. Prediction tools that are available all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool reports a benign outcome. High‑accuracy assessments are consistent: AlphaMissense‑Optimized is “Uncertain,” SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. **Based on the aggregate predictions, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 2 | 6-33438435-T-C | 1 | 6.20e-7 | -12.399 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.801 | Likely Pathogenic | 0.2094 | 0.1950 | 3.47 | Destabilizing | 0.1 | 3.10 | Destabilizing | 3.29 | Destabilizing | 1.84 | Destabilizing | -3.85 | Deleterious | 0.994 | Probably Damaging | 0.985 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 3.37 | 31 | -1 | -1 | -2.6 | -30.09 | 214.6 | 47.1 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the hydrophilic side chain of Thr468 does not pack favorably in the hydrophobic niche, and the methionine-aromatic stacking is lost. Although the hydroxyl group of Thr468 forms an H-bond with the backbone carbonyl group of Phe464, the integrity of the α helix is not affected in the simulations. No large-scale structural changes are observed during the variant simulations; however, due to the importance of hydrophobic packing, the effects could be more pronounced during protein folding. | |||||||||
| c.1403T>G | M468R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468R is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -16.180 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.837 | Likely Pathogenic | 0.1717 | 0.0637 | 2.66 | Destabilizing | 0.2 | 2.23 | Destabilizing | 2.45 | Destabilizing | 2.43 | Destabilizing | -4.64 | Deleterious | 0.939 | Possibly Damaging | 0.943 | Probably Damaging | -1.34 | Pathogenic | 0.00 | Affected | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||
| c.1404G>A | M468I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M468I is listed in ClinVar with an uncertain significance (ClinVar ID 3657719.0) and is present in gnomAD (6‑33438436‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, and SIFT, while pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools report uncertainty: AlphaMissense‑Optimized and Rosetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates a pathogenic impact for M468I, which does not contradict the ClinVar uncertain status but suggests a likely pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 1 | 6-33438436-G-A | 1 | 6.20e-7 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.508 | Likely Pathogenic | 0.1369 | 0.3354 | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||
| c.1404G>C | M468I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468I is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—classify the change as pathogenic. Two methods report uncertainty: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates a pathogenic effect. AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for M468I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.508 | Likely Pathogenic | 0.1369 | 0.3354 | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||
| c.1404G>T | M468I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468I is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default—classify the change as pathogenic. Two methods report uncertainty: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also indicates a pathogenic effect; AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for M468I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -8.583 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.510 | Likely Pathogenic | 0.1369 | 0.3354 | 2.53 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.21 | Destabilizing | 0.37 | Likely Benign | -1.06 | Neutral | 0.748 | Possibly Damaging | 0.886 | Possibly Damaging | -1.10 | Pathogenic | 0.07 | Tolerated | 3.37 | 31 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||
| c.1405G>A | A469T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A469T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). The high‑accuracy subset shows AlphaMissense‑Optimized as benign, whereas SGM Consensus and Foldetta both predict pathogenic. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | Uncertain | 1 | -9.540 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.527 | Likely Pathogenic | 0.1005 | 0.5884 | 2.26 | Destabilizing | 0.1 | 1.90 | Ambiguous | 2.08 | Destabilizing | 0.34 | Likely Benign | -1.46 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.21 | Pathogenic | 0.42 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||
| c.1405G>C | A469P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the overwhelming consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -16.072 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.774 | Likely Pathogenic | 0.1606 | 0.4092 | 5.06 | Destabilizing | 0.3 | 8.83 | Destabilizing | 6.95 | Destabilizing | 1.02 | Destabilizing | -2.69 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.33 | Pathogenic | 0.21 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1405G>T | A469S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Foldetta, and premPS give uncertain or inconclusive results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts a benign change; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -9.051 | Likely Pathogenic | 0.627 | Likely Pathogenic | Likely Benign | 0.558 | Likely Pathogenic | 0.2113 | 0.4505 | 0.86 | Ambiguous | 0.0 | 2.10 | Destabilizing | 1.48 | Ambiguous | 0.81 | Ambiguous | -1.53 | Neutral | 0.953 | Possibly Damaging | 0.985 | Probably Damaging | -1.30 | Pathogenic | 0.41 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1406C>A | A469D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction from SIFT, and a consensus of pathogenic predictions from the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus). High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | Uncertain | 1 | -14.643 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.738 | Likely Pathogenic | 0.1372 | 0.1583 | 5.09 | Destabilizing | 0.2 | 4.16 | Destabilizing | 4.63 | Destabilizing | 1.68 | Destabilizing | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.34 | Pathogenic | 0.21 | Tolerated | 3.37 | 34 | 0 | -2 | -5.3 | 44.01 | 237.0 | -58.2 | -0.2 | 0.1 | 0.8 | 0.1 | X | X | Potentially Pathogenic | The methyl group of Ala469, located in an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Trp572, Leu588, Met470) in an inter-helix space formed by two other α helices (res. Glu582–Ser604, res. Arg563–Gly580). In the variant simulations, Asp469 introduces a negatively charged and bulky side chain into the hydrophobic niche. Consequently, the side chain of Asp469 rotates outward, allowing the carboxylate group to form a salt bridge with the guanidinium group of Arg575 on the protein surface. This interaction affects the continuity of the parent α helix (Ala461–Phe476). Due to the importance of hydrophobic packing, the structural effects could be more pronounced during actual protein folding. | |||||||||||
| c.1406C>G | A469G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A469G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy methods give mixed results: AlphaMissense‑Optimized indicates benign, Foldetta indicates pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of tools (12 vs. 4) predict pathogenicity, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -4.438 | Likely Benign | 0.733 | Likely Pathogenic | Likely Benign | 0.569 | Likely Pathogenic | 0.1797 | 0.3078 | 1.99 | Ambiguous | 0.1 | 2.22 | Destabilizing | 2.11 | Destabilizing | 1.01 | Destabilizing | -2.42 | Neutral | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.32 | Pathogenic | 0.37 | Tolerated | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||
| c.1406C>T | A469V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A469V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect comprise FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and Foldetta; premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts pathogenic. With seven tools supporting pathogenicity versus four supporting benignity, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -8.858 | Likely Pathogenic | 0.459 | Ambiguous | Likely Benign | 0.426 | Likely Benign | 0.0827 | 0.5421 | 2.30 | Destabilizing | 0.4 | 2.66 | Destabilizing | 2.48 | Destabilizing | -0.77 | Ambiguous | 0.26 | Neutral | 0.997 | Probably Damaging | 0.976 | Probably Damaging | -1.20 | Pathogenic | 0.60 | Tolerated | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||
| c.1408A>C | M470L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470L is listed in ClinVar as benign (ClinVar ID 536996.0) and is present in gnomAD (variant ID 6‑33438440‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from SIFT and AlphaMissense‑Optimized, while pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No definitive folding‑stability change is reported by FoldX or Rosetta individually. Overall, the majority of predictive algorithms favor a pathogenic effect, directly contradicting the benign classification in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Likely Benign | 1 | 6-33438440-A-C | 1 | 6.20e-7 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.678 | Likely Pathogenic | 0.1192 | 0.4071 | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | |||||||||
| c.1408A>G | M470V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from most in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all score it as deleterious. Only two tools—SIFT and AlphaMissense‑Optimized—classify it as benign, while Rosetta and AlphaMissense‑Default remain inconclusive. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized reports a benign outcome, but the SGM‑Consensus (derived from a majority of pathogenic calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining pathogenic FoldX with uncertain Rosetta) both predict pathogenicity. Overall, the preponderance of evidence supports a likely pathogenic classification, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Uncertain | 1 | -8.856 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.770 | Likely Pathogenic | 0.2710 | 0.3256 | 2.73 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.31 | Destabilizing | 1.31 | Destabilizing | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.20 | Pathogenic | 0.15 | Tolerated | 3.37 | 34 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||
| c.1408A>T | M470L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470L is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on benign effect include SIFT and AlphaMissense‑Optimized. Tools that agree on pathogenic effect include SGM Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -8.993 | Likely Pathogenic | 0.406 | Ambiguous | Likely Benign | 0.678 | Likely Pathogenic | 0.1192 | 0.4071 | 0.73 | Ambiguous | 0.1 | 0.84 | Ambiguous | 0.79 | Ambiguous | 1.04 | Destabilizing | -2.72 | Deleterious | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -1.22 | Pathogenic | 0.16 | Tolerated | 3.37 | 34 | 4 | 2 | 1.9 | -18.03 | 225.3 | 17.9 | 0.0 | 0.0 | -0.8 | 0.5 | X | Potentially Benign | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, Met470 also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the iso-butyl side chain of Leu470 packs similarly with the hydrophobic residues as methionine, resulting in no negative effects on the protein structure during the simulation. | ||||||||||||||
| c.1409T>A | M470K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M470K is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools cluster into two groups: the single benign call comes from SIFT, while all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label the change as pathogenic or likely pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports pathogenic. Thus, the variant is most likely pathogenic based on the consensus of available predictions, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -14.327 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.823 | Likely Pathogenic | 0.1157 | 0.0656 | 2.77 | Destabilizing | 0.1 | 2.67 | Destabilizing | 2.72 | Destabilizing | 1.55 | Destabilizing | -5.42 | Deleterious | 0.923 | Possibly Damaging | 0.922 | Probably Damaging | -1.06 | Pathogenic | 0.20 | Tolerated | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||
| c.1409T>C | M470T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding‑stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | Uncertain | 1 | -8.104 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.763 | Likely Pathogenic | 0.1782 | 0.1950 | 3.19 | Destabilizing | 0.1 | 2.68 | Destabilizing | 2.94 | Destabilizing | 1.49 | Destabilizing | -5.30 | Deleterious | 0.996 | Probably Damaging | 0.985 | Probably Damaging | -1.08 | Pathogenic | 0.24 | Tolerated | 3.37 | 34 | -1 | -1 | -2.6 | -30.09 | 213.8 | 46.5 | 0.0 | 0.0 | -0.2 | 0.2 | X | X | Potentially Pathogenic | The thioether group of Met470, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues in the inter-helix space (e.g., Val473, Leu558, Cys576, Trp572) formed by two other α helices (res. Ser604–Arg581, res. Pro562–Arg579). In the WT simulations, the Met470 side chain also packs against the positively charged guanidinium groups of Arg575, Arg429, and Arg579, which form salt bridges with the negatively charged carboxylate groups of the Asp474 and Asp467 side chains at the protein surface. In the variant simulations, the hydroxyl group of the Thr470 side chain forms an H-bond with the backbone carbonyl group of Ser466 in the α helix, potentially lowering its structural integrity. Importantly, the hydroxyl group of Thr470 also forms an H-bond with the guanidinium group of Arg575, which helps it form a more permanent salt bridge with Asp467. | |||||||||||
| c.1409T>G | M470R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M470R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -13.161 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.823 | Likely Pathogenic | 0.1399 | 0.0757 | 2.75 | Destabilizing | 0.1 | 2.75 | Destabilizing | 2.75 | Destabilizing | 1.57 | Destabilizing | -5.47 | Deleterious | 0.963 | Probably Damaging | 0.943 | Probably Damaging | -1.19 | Pathogenic | 0.17 | Tolerated | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||
| c.1410G>A | M470I 2D AIThe SynGAP1 missense variant M470I is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic impact. Predictions marked as uncertain (AlphaMissense‑Optimized, FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta are uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -9.474 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.747 | Likely Pathogenic | 0.1061 | 0.2827 | 1.53 | Ambiguous | 0.7 | 1.34 | Ambiguous | 1.44 | Ambiguous | 0.84 | Ambiguous | -3.55 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.26 | Pathogenic | 0.07 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||
| c.1410G>C | M470I 2D AIThe SynGAP1 missense variant M470I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include only SIFT, whereas the remaining evidence—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict pathogenicity. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Overall, the preponderance of predictions supports a pathogenic effect for M470I, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -9.474 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.747 | Likely Pathogenic | 0.1061 | 0.2827 | 1.53 | Ambiguous | 0.7 | 1.34 | Ambiguous | 1.44 | Ambiguous | 0.84 | Ambiguous | -3.55 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.26 | Pathogenic | 0.07 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||
| c.1410G>T | M470I 2D AIThe SynGAP1 missense variant M470I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include only SIFT, whereas the remaining evidence—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict pathogenicity. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Overall, the preponderance of predictions supports a pathogenic effect for M470I, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.351497 | Uncertain | 0.908 | 0.272 | 0.000 | -9.474 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.747 | Likely Pathogenic | 0.1061 | 0.2827 | 1.53 | Ambiguous | 0.7 | 1.34 | Ambiguous | 1.44 | Ambiguous | 0.84 | Ambiguous | -3.55 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.26 | Pathogenic | 0.07 | Tolerated | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||
| c.1411T>A | S471T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -5.780 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.257 | Likely Benign | 0.1307 | 0.5046 | 0.59 | Ambiguous | 0.2 | -0.47 | Likely Benign | 0.06 | Likely Benign | 0.20 | Likely Benign | -1.96 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.18 | Pathogenic | 0.09 | Tolerated | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1411T>C | S471P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only polyPhen‑2 HumVar, whereas the remaining evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -12.379 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.530 | Likely Pathogenic | 0.2007 | 0.4769 | 3.65 | Destabilizing | 0.2 | 9.24 | Destabilizing | 6.45 | Destabilizing | 0.84 | Ambiguous | -4.03 | Deleterious | 0.552 | Possibly Damaging | 0.141 | Benign | -1.31 | Pathogenic | 0.05 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||
| c.1411T>G | S471A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471A is not reported in ClinVar and is absent from gnomAD. Across the spectrum of in‑silico predictors, the majority (REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) classify the change as benign, whereas only FATHMM predicts it as pathogenic; Rosetta is inconclusive. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. No evidence suggests pathogenicity, and the predictions do not contradict the absence of ClinVar annotation. Therefore, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -5.516 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.252 | Likely Benign | 0.4439 | 0.3691 | 0.11 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.25 | Likely Benign | 0.23 | Likely Benign | -1.93 | Neutral | 0.010 | Benign | 0.037 | Benign | -1.22 | Pathogenic | 0.29 | Tolerated | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| c.1412C>A | S471Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, premPS, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized scores the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, returns an uncertain stability change. No evidence from ClinVar contradicts these computational assessments. Overall, the preponderance of pathogenic predictions and the SGM Consensus suggest the variant is most likely pathogenic, consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -11.257 | Likely Pathogenic | 0.493 | Ambiguous | Likely Benign | 0.446 | Likely Benign | 0.0607 | 0.4417 | -0.33 | Likely Benign | 0.1 | -1.31 | Ambiguous | -0.82 | Ambiguous | 0.19 | Likely Benign | -4.79 | Deleterious | 0.980 | Probably Damaging | 0.584 | Possibly Damaging | -1.27 | Pathogenic | 0.03 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.1412C>G | S471C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471C is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33438444‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of predictions (10 benign vs. 3 pathogenic) indicate that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no reported pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | 6-33438444-C-G | 1 | 6.20e-7 | -3.454 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.273 | Likely Benign | 0.1048 | 0.4913 | 0.36 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.16 | Likely Benign | 0.07 | Likely Benign | -2.90 | Deleterious | 0.000 | Benign | 0.001 | Benign | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 34 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||
| c.1412C>T | S471F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining tools—AlphaMissense‑Default, FoldX, Rosetta, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Taken together, the majority of evidence points toward a pathogenic impact for S471F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -10.777 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | 0.423 | Likely Benign | 0.0553 | 0.4691 | -0.54 | Ambiguous | 0.1 | -1.51 | Ambiguous | -1.03 | Ambiguous | 0.12 | Likely Benign | -4.75 | Deleterious | 0.942 | Possibly Damaging | 0.487 | Possibly Damaging | -1.26 | Pathogenic | 0.02 | Affected | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||
| c.1414G>A | E472K 2D AIThe SynGAP1 missense variant E472K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS, which is listed as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.214 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.670 | Likely Pathogenic | 0.3077 | 0.5651 | 2.01 | Destabilizing | 1.2 | 3.23 | Destabilizing | 2.62 | Destabilizing | 0.78 | Ambiguous | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 2.33 | Pathogenic | 0.03 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1414G>C | E472Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only Foldetta, which classifies the variant as benign. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive predictions come from FoldX, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact for E472Q, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -13.760 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.555 | Likely Pathogenic | 0.1388 | 0.5726 | 1.34 | Ambiguous | 0.3 | -0.67 | Ambiguous | 0.34 | Likely Benign | 0.89 | Ambiguous | -2.95 | Deleterious | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 2.39 | Pathogenic | 0.01 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1415A>C | E472A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all these methods uniformly classify the change as deleterious. Tools that are inconclusive or uncertain for this variant are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic outcome, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, while Foldetta’s stability analysis remains uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect for E472A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.356 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.732 | Likely Pathogenic | 0.4639 | 0.6315 | 1.81 | Ambiguous | 0.3 | 0.67 | Ambiguous | 1.24 | Ambiguous | 0.69 | Ambiguous | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.32 | Pathogenic | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1415A>G | E472G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic or likely pathogenic. Only premPS predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.239 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.744 | Likely Pathogenic | 0.3343 | 0.4950 | 3.06 | Destabilizing | 0.2 | 2.86 | Destabilizing | 2.96 | Destabilizing | 0.24 | Likely Benign | -6.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1415A>T | E472V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E472V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Foldetta and premPS, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. No prediction or folding‑stability result is missing or inconclusive; uncertain outputs from FoldX and Rosetta are treated as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -14.957 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.733 | Likely Pathogenic | 0.0881 | 0.6347 | 1.05 | Ambiguous | 0.3 | -0.64 | Ambiguous | 0.21 | Likely Benign | 0.37 | Likely Benign | -6.90 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1416G>C | E472D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472D is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL and SIFT, whereas the majority of tools—SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict pathogenicity. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability estimates. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (derived from the four high‑confidence predictors) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E472D, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -9.798 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.304 | Likely Benign | 0.1975 | 0.3918 | 1.27 | Ambiguous | 0.3 | 1.99 | Ambiguous | 1.63 | Ambiguous | 1.00 | Destabilizing | -2.75 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.43 | Pathogenic | 0.06 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1416G>T | E472D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), FATHMM, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, Foldetta) yield uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -9.798 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.303 | Likely Benign | 0.1975 | 0.3918 | 1.27 | Ambiguous | 0.3 | 1.99 | Ambiguous | 1.63 | Ambiguous | 1.00 | Destabilizing | -2.75 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 2.43 | Pathogenic | 0.06 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1417G>A | V473I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438449‑G‑A). Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are provided by both polyPhen‑2 HumDiv and HumVar. Predictions that are inconclusive are AlphaMissense‑Default, ESM1b, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority, and Foldetta is uncertain. Overall, the balance of evidence favors a benign effect for V473I, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | Uncertain | 1 | 6-33438449-G-A | 1 | 6.20e-7 | -7.481 | In-Between | 0.418 | Ambiguous | Likely Benign | 0.203 | Likely Benign | 0.0568 | 0.3335 | -0.12 | Likely Benign | 0.0 | 1.20 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | -0.91 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.74 | Benign | 0.18 | Tolerated | 3.37 | 34 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||
| c.1417G>C | V473L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and Foldetta, while those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools (seven pathogenic vs. six benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -9.073 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.336 | Likely Benign | 0.0708 | 0.3921 | -0.29 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.41 | Likely Benign | 0.35 | Likely Benign | -2.85 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.43 | Benign | 0.21 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1417G>T | V473L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and Foldetta, while those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools (seven pathogenic vs. six benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -9.073 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 0.335 | Likely Benign | 0.0708 | 0.3921 | -0.29 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.41 | Likely Benign | 0.35 | Likely Benign | -2.85 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.43 | Benign | 0.21 | Tolerated | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1418T>A | V473E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: all evaluated algorithms except FATHMM predict pathogenicity, while FATHMM alone predicts benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the consensus of the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -15.296 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.664 | Likely Pathogenic | 0.0903 | 0.1396 | 3.20 | Destabilizing | 0.2 | 2.24 | Destabilizing | 2.72 | Destabilizing | 2.22 | Destabilizing | -5.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||
| c.1418T>C | V473A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V473A missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are all uncertain or unavailable, providing no decisive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions support a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation (no contradiction). Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -10.867 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.485 | Likely Benign | 0.2529 | 0.2521 | 1.88 | Ambiguous | 0.0 | 1.76 | Ambiguous | 1.82 | Ambiguous | 2.17 | Destabilizing | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||
| c.1418T>G | V473G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) votes pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective evidence, and this conclusion does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -14.782 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.683 | Likely Pathogenic | 0.1885 | 0.2567 | 3.45 | Destabilizing | 0.0 | 3.40 | Destabilizing | 3.43 | Destabilizing | 2.69 | Destabilizing | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||
| c.1420G>A | D474N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and SIFT, whereas pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further indicate that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. AlphaMissense‑Optimized is inconclusive and therefore not considered evidence. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -10.696 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | 0.542 | Likely Pathogenic | 0.1047 | 0.4135 | 0.13 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.22 | Likely Benign | 0.06 | Likely Benign | -4.21 | Deleterious | 0.992 | Probably Damaging | 0.990 | Probably Damaging | -1.18 | Pathogenic | 0.08 | Tolerated | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1420G>C | D474H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D474H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Pathogenic. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Overall, the preponderance of evidence points to a pathogenic effect for D474H, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -13.610 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.739 | Likely Pathogenic | 0.1398 | 0.4619 | 0.66 | Ambiguous | 0.0 | 0.00 | Likely Benign | 0.33 | Likely Benign | 0.27 | Likely Benign | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.02 | Affected | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.1420G>T | D474Y 2D AIThe SynGAP1 missense variant D474Y is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, and premPS, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the preponderance of evidence points to a pathogenic effect for D474Y. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -14.647 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.864 | Likely Pathogenic | 0.0493 | 0.4237 | 0.27 | Likely Benign | 0.5 | -0.74 | Ambiguous | -0.24 | Likely Benign | 0.20 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.30 | Pathogenic | 0.01 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.1421A>C | D474A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and SIFT, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as Pathogenic, SGM Consensus as Likely Pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -11.082 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.757 | Likely Pathogenic | 0.3265 | 0.4354 | 0.08 | Likely Benign | 0.0 | 0.15 | Likely Benign | 0.12 | Likely Benign | 0.17 | Likely Benign | -6.73 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.22 | Pathogenic | 0.22 | Tolerated | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.1421A>G | D474G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D474G is not reported in ClinVar and is present in gnomAD (ID 6‑33438453‑A‑G). Functional prediction tools show a split: benign calls come from FoldX, Foldetta, premPS, and SIFT, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta remains uncertain. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized and a pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | 6-33438453-A-G | 1 | 6.20e-7 | -11.215 | Likely Pathogenic | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.823 | Likely Pathogenic | 0.3245 | 0.4933 | -0.38 | Likely Benign | 0.0 | 0.82 | Ambiguous | 0.22 | Likely Benign | 0.44 | Likely Benign | -6.13 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.28 | Pathogenic | 0.07 | Tolerated | 3.37 | 34 | -1 | 1 | 3.1 | -58.04 | ||||||||||||||||||||
| c.1421A>T | D474V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -12.999 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.866 | Likely Pathogenic | 0.0694 | 0.4510 | 0.77 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.48 | Likely Benign | 0.18 | Likely Benign | -7.69 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.30 | Pathogenic | 0.04 | Affected | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.1422C>A | D474E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas a separate group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools are uncertain: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, but the high‑accuracy tools provide conflicting evidence. Thus, the variant is most likely pathogenic based on the current computational predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -7.079 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | 0.408 | Likely Benign | 0.1233 | 0.4287 | -0.35 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.15 | Likely Benign | 0.10 | Likely Benign | -3.01 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -1.11 | Pathogenic | 0.20 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1422C>G | D474E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D474E is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT, while those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Two tools—AlphaMissense‑Optimized and ESM1b—return uncertain results. High‑accuracy assessments show SGM‑Consensus predicting a likely pathogenic outcome, AlphaMissense‑Optimized remaining uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of consensus tools lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -7.079 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | 0.408 | Likely Benign | 0.1233 | 0.4287 | -0.35 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.15 | Likely Benign | 0.10 | Likely Benign | -3.01 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -1.11 | Pathogenic | 0.20 | Tolerated | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1423C>G | R475G 2D AIThe SynGAP1 missense variant R475G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenicity. Only Rosetta and AlphaMissense‑Optimized return uncertain results, and no tool predicts a benign outcome. High‑accuracy methods provide a consistent view: AlphaMissense‑Optimized is uncertain, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Taken together, the overwhelming majority of evidence supports a pathogenic classification for R475G, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -14.466 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.697 | Likely Pathogenic | 0.2779 | 0.2310 | 2.39 | Destabilizing | 1.0 | 1.64 | Ambiguous | 2.02 | Destabilizing | 1.11 | Destabilizing | -6.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.1423C>T | R475W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475W is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33438455‑C‑T). Prediction tools that agree on a benign effect include only Foldetta, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) uniformly predict a pathogenic impact; FoldX, Rosetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification but suggests that the variant is more likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | Uncertain | 1 | 6-33438455-C-T | 1 | 6.20e-7 | -13.235 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.725 | Likely Pathogenic | 0.1231 | 0.2785 | 1.44 | Ambiguous | 0.4 | -0.92 | Ambiguous | 0.26 | Likely Benign | 0.56 | Ambiguous | -7.56 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | 3.39 | 28 | 2 | -3 | 3.6 | 30.03 | 266.9 | 39.6 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation.In the variant simulations, Trp475 moves and stacks with Arg479 on the proceeding α-α loop, disrupting the terminal end of the α-helix. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||
| c.1424G>A | R475Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475Q is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438456‑G‑A). Prediction tools that indicate a benign effect include AlphaMissense‑Optimized, Foldetta, and Rosetta. Those that predict a pathogenic effect comprise SGM Consensus, SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points toward a pathogenic impact, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | Uncertain | 2 | 6-33438456-G-A | 5 | 3.10e-6 | -12.087 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.632 | Likely Pathogenic | 0.2190 | 0.1926 | 0.71 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.42 | Likely Benign | 0.82 | Ambiguous | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.39 | 28 | 1 | 1 | 1.0 | -28.06 | 253.6 | 52.7 | 0.0 | 0.0 | -0.8 | 0.0 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation. In the variant simulations, Asn475 forms a hydrogen bond with Arg479 on the proceeding α-α loop. The absence of Phe476/Arg475 stacking and the Arg475-Glu472 salt bridge weakens the integrity of the terminal end of the α-helix during the variant simulations. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||
| c.1424G>C | R475P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: benign‑predicting algorithms are not present, while pathogenic‑predicting tools—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all classify the substitution as pathogenic. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Consequently, the variant is most likely pathogenic based on the available computational evidence, and this assessment does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -16.637 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.835 | Likely Pathogenic | 0.1943 | 0.3295 | 2.93 | Destabilizing | 0.4 | 5.40 | Destabilizing | 4.17 | Destabilizing | 1.02 | Destabilizing | -6.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.43 | Pathogenic | 0.00 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1424G>T | R475L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R475L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score, whereas only Rosetta predicts a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. With the preponderance of pathogenic calls and no conflicting evidence from ClinVar or population databases, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | -13.074 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 0.806 | Likely Pathogenic | 0.1580 | 0.3428 | 1.49 | Ambiguous | 0.4 | -0.47 | Likely Benign | 0.51 | Ambiguous | 0.55 | Ambiguous | -6.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.40 | Pathogenic | 0.00 | Affected | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1426T>A | F476I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F476I has no ClinVar entry and is not reported in gnomAD. Functional prediction tools fall into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, and FATHMM; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—remains inconclusive and is treated as unavailable. With seven tools indicating pathogenicity versus five indicating benign, and two high‑accuracy tools supporting pathogenicity, the evidence points to a likely pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no record for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.617 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.239 | Likely Benign | 0.1383 | 0.2202 | 3.90 | Destabilizing | 0.1 | 3.09 | Destabilizing | 3.50 | Destabilizing | 0.39 | Likely Benign | -1.23 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 3.50 | Benign | 0.37 | Tolerated | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||
| c.1426T>C | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No other tools provide definitive evidence. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.196 | Likely Benign | 0.1653 | 0.2916 | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||
| c.1426T>G | F476V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F476V variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that agree on a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and Foldetta. Tools with uncertain or mixed outputs are Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic impact. Overall, the majority of evidence points toward a pathogenic effect. The variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.329 | Likely Pathogenic | 0.918 | Likely Pathogenic | Ambiguous | 0.353 | Likely Benign | 0.1478 | 0.2251 | 3.01 | Destabilizing | 0.2 | 1.90 | Ambiguous | 2.46 | Destabilizing | 0.64 | Ambiguous | -1.63 | Neutral | 0.996 | Probably Damaging | 0.993 | Probably Damaging | 3.49 | Benign | 0.53 | Tolerated | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||
| c.1427T>A | F476Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta predicts a benign outcome. Overall, the balance of evidence leans toward a benign impact for F476Y, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -9.707 | Likely Pathogenic | 0.576 | Likely Pathogenic | Likely Benign | 0.169 | Likely Benign | 0.1109 | 0.1568 | 0.50 | Ambiguous | 0.2 | 0.30 | Likely Benign | 0.40 | Likely Benign | 1.10 | Destabilizing | -1.10 | Neutral | 0.965 | Probably Damaging | 0.919 | Probably Damaging | 3.46 | Benign | 0.90 | Tolerated | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||
| c.1427T>C | F476S 2D AIThe SynGAP1 missense variant F476S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of pathogenic and benign signals. Overall, the balance of evidence favors a pathogenic effect for F476S, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -12.675 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.278 | Likely Benign | 0.3387 | 0.0558 | 3.02 | Destabilizing | 0.9 | 4.07 | Destabilizing | 3.55 | Destabilizing | 1.23 | Destabilizing | -2.33 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.56 | Benign | 0.44 | Tolerated | -3 | -2 | -3.6 | -60.10 | ||||||||||||||||||||||||||
| c.1427T>G | F476C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476C is catalogued in gnomAD (ID 6‑33438459‑T‑G) but has no ClinVar entry. Functional prediction tools split in two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, seven tools predict pathogenicity versus six predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | 6-33438459-T-G | -9.270 | Likely Pathogenic | 0.745 | Likely Pathogenic | Likely Benign | 0.280 | Likely Benign | 0.2051 | 0.1251 | 2.05 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.34 | Destabilizing | -0.30 | Likely Benign | 2.69 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.46 | Benign | 0.83 | Tolerated | 3.40 | 22 | -2 | -4 | -0.3 | -44.04 | |||||||||||||||||||||||
| c.1428C>A | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No other tools provide definitive evidence. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.180 | Likely Benign | 0.1653 | 0.2916 | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||||
| c.1428C>G | F476L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F476L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438460‑C‑G). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that returned uncertain results—FoldX, Rosetta, Foldetta, and premPS—do not contribute to the assessment. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, with two pathogenic and two benign calls; Foldetta also reports an uncertain stability change. Overall, the balance of evidence favors a pathogenic effect for F476L, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.397815 | Uncertain | 0.821 | 0.250 | 0.000 | Uncertain | 2 | 6-33438460-C-G | 4 | 2.48e-6 | -10.109 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.180 | Likely Benign | 0.1653 | 0.2916 | 1.00 | Ambiguous | 0.1 | 1.04 | Ambiguous | 1.02 | Ambiguous | 0.75 | Ambiguous | -1.10 | Neutral | 0.997 | Probably Damaging | 0.978 | Probably Damaging | 3.53 | Benign | 0.60 | Tolerated | 3.40 | 22 | 2 | 0 | 1.0 | -34.02 | 235.9 | 16.1 | 0.0 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | In the WT simulations, the phenyl ring of Phe476, located at the end of an α-helix (res. Ala461-Phe476), packs with the hydrophobic side chains of Leu482 and Ile483. Additionally, Phe476 stacks with the Arg475 side chain on the preceding α-α loop connecting the two α-helices (res. Ala461-Phe476 and res. Leu489-Glu519) near the GAP-Ras interface.In the variant simulations, Leu476 can maintain hydrophobic packing with neighboring residues, although not as efficiently as the phenylalanine in the WT system. The absence of Phe476/Arg475 stacking weakens the integrity of the α-helix end in the variant simulations. Nonetheless, no large-scale adverse effects are observed in the simulations. Lastly, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||||
| c.1429A>C | M477L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome; premPS is uncertain and therefore not counted as evidence. High‑accuracy assessments are consistent: AlphaMissense‑Optimized reports Benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Overall, the preponderance of evidence supports a benign classification for M477L, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -4.772 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.236 | Likely Benign | 0.1586 | 0.4220 | 0.10 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.15 | Likely Benign | 0.58 | Ambiguous | -1.25 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.18 | Pathogenic | 0.17 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1429A>G | M477V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477V is listed in ClinVar with no submitted interpretation and is present in the gnomAD database (variant ID 6‑33438461‑A‑G). Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only two tools predict a pathogenic outcome: polyPhen2_HumDiv and FATHMM. Predictions from FoldX and Foldetta are uncertain. High‑accuracy methods reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta remains inconclusive. Taken together, the majority of evidence supports a benign classification for M477V, and this assessment does not contradict the ClinVar status, which currently has no pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | 6-33438461-A-G | 1 | 6.20e-7 | -3.995 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.209 | Likely Benign | 0.3093 | 0.3445 | 1.64 | Ambiguous | 0.3 | 0.42 | Likely Benign | 1.03 | Ambiguous | 0.24 | Likely Benign | -1.04 | Neutral | 0.716 | Possibly Damaging | 0.204 | Benign | -1.19 | Pathogenic | 0.22 | Tolerated | 3.37 | 34 | 1 | 2 | 2.3 | -32.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||
| c.1429A>T | M477L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly indicate a benign effect. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the available evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -4.772 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.236 | Likely Benign | 0.1586 | 0.4220 | 0.10 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.15 | Likely Benign | 0.58 | Ambiguous | -1.25 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.18 | Pathogenic | 0.17 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1430T>A | M477K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS and FATHMM. Predictions that are uncertain or inconclusive are FoldX, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to mixed or uncertain inputs. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this conclusion does not contradict the current ClinVar status, which contains no report of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -7.519 | In-Between | 0.553 | Ambiguous | Likely Benign | 0.371 | Likely Benign | 0.1817 | 0.0847 | 0.54 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.46 | Likely Benign | 1.12 | Destabilizing | -1.32 | Neutral | 0.254 | Benign | 0.122 | Benign | -1.15 | Pathogenic | 0.14 | Tolerated | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||
| c.1430T>C | M477T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477T has no ClinVar entry and is present in gnomAD (ID 6‑33438462‑T‑C). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign (2 benign vs. 1 pathogenic votes); Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | 6-33438462-T-C | 2 | 1.24e-6 | -2.509 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.273 | Likely Benign | 0.2177 | 0.1950 | 1.62 | Ambiguous | 0.2 | 0.16 | Likely Benign | 0.89 | Ambiguous | 0.51 | Ambiguous | -1.33 | Neutral | 0.765 | Possibly Damaging | 0.363 | Benign | -1.10 | Pathogenic | 0.40 | Tolerated | 3.37 | 34 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||
| c.1430T>G | M477R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and FATHMM. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain and is not taken as evidence. Overall, the majority of reliable predictors indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -6.786 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.442 | Likely Benign | 0.1901 | 0.0828 | 0.48 | Likely Benign | 0.2 | 0.77 | Ambiguous | 0.63 | Ambiguous | 1.24 | Destabilizing | -1.12 | Neutral | 0.720 | Possibly Damaging | 0.242 | Benign | -1.22 | Pathogenic | 0.11 | Tolerated | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||
| c.1431G>A | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.291 | Likely Benign | 0.1368 | 0.3176 | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1431G>C | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.290 | Likely Benign | 0.1368 | 0.3176 | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1431G>T | M477I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while FoldX, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -2.662 | Likely Benign | 0.467 | Ambiguous | Likely Benign | 0.291 | Likely Benign | 0.1368 | 0.3176 | 0.72 | Ambiguous | 0.1 | 0.36 | Likely Benign | 0.54 | Ambiguous | 0.45 | Likely Benign | -1.57 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.21 | Pathogenic | 0.09 | Tolerated | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1432G>A | E478K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478K is not reported in ClinVar (ClinVar ID: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as benign. Overall, the majority of evidence (eight benign versus five pathogenic predictions) points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -12.654 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 0.309 | Likely Benign | 0.2066 | 0.6192 | 0.23 | Likely Benign | 0.0 | 0.12 | Likely Benign | 0.18 | Likely Benign | -0.02 | Likely Benign | -3.45 | Deleterious | 0.320 | Benign | 0.117 | Benign | 3.49 | Benign | 0.05 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1432G>C | E478Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478Q is listed in gnomAD (ID 6‑33438464‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑vs‑2 split. Overall, the majority of evidence (nine benign vs three pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | 6-33438464-G-C | 1 | 6.20e-7 | -9.881 | Likely Pathogenic | 0.603 | Likely Pathogenic | Likely Benign | 0.222 | Likely Benign | 0.1027 | 0.5867 | -0.04 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.14 | Likely Benign | 0.07 | Likely Benign | -2.49 | Neutral | 0.623 | Possibly Damaging | 0.199 | Benign | 3.40 | Benign | 0.14 | Tolerated | 3.37 | 34 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||
| c.1433A>C | E478A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E478A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions are missing or inconclusive. Overall, the majority of high‑confidence tools lean toward a benign classification, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -8.499 | Likely Pathogenic | 0.612 | Likely Pathogenic | Likely Benign | 0.342 | Likely Benign | 0.3516 | 0.5847 | 0.46 | Likely Benign | 0.0 | 0.45 | Likely Benign | 0.46 | Likely Benign | 0.02 | Likely Benign | -4.74 | Deleterious | 0.585 | Possibly Damaging | 0.505 | Possibly Damaging | 3.42 | Benign | 0.05 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1433A>G | E478G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E478G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. Uncertain predictions come from Rosetta, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to equal benign and pathogenic signals and two uncertain calls; Foldetta likewise yields an uncertain result. Overall, the majority of evaluated tools (seven benign vs. two pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -7.897 | In-Between | 0.418 | Ambiguous | Likely Benign | 0.306 | Likely Benign | 0.2758 | 0.5572 | 0.40 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.57 | Ambiguous | 0.02 | Likely Benign | -4.91 | Deleterious | 0.923 | Possibly Damaging | 0.427 | Benign | 3.41 | Benign | 0.15 | Tolerated | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||
| c.1433A>T | E478V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E478V missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, Rosetta, polyPhen‑2 (HumDiv and HumVar), FATHMM, and premPS; pathogenic predictions from SGM‑Consensus, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: FoldX (uncertain) and AlphaMissense‑Optimized (uncertain). High‑accuracy assessments further split the signal: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. With six benign versus five pathogenic calls and no ClinVar evidence, the overall evidence slightly favors a benign interpretation, and there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -10.322 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.385 | Likely Benign | 0.0586 | 0.6604 | 0.55 | Ambiguous | 0.0 | 0.33 | Likely Benign | 0.44 | Likely Benign | 0.04 | Likely Benign | -5.84 | Deleterious | 0.434 | Benign | 0.199 | Benign | 3.35 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1434A>C | E478D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -1.004 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.175 | Likely Benign | 0.1768 | 0.3315 | -0.04 | Likely Benign | 0.0 | -0.65 | Ambiguous | -0.35 | Likely Benign | -0.28 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.53 | Benign | 0.70 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1434A>T | E478D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E478D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -1.004 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.175 | Likely Benign | 0.1768 | 0.3315 | -0.04 | Likely Benign | 0.0 | -0.65 | Ambiguous | -0.35 | Likely Benign | -0.28 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.53 | Benign | 0.70 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1435C>G | R479G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479G is reported in gnomAD (ID 6-33438467-C-G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta, which assess protein‑folding stability, returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as inconclusive. Overall, the majority of computational evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Therefore, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | 6-33438467-C-G | 1 | 6.20e-7 | -8.600 | Likely Pathogenic | 0.624 | Likely Pathogenic | Likely Benign | 0.228 | Likely Benign | 0.2911 | 0.2707 | 0.97 | Ambiguous | 0.0 | 2.51 | Destabilizing | 1.74 | Ambiguous | 0.71 | Ambiguous | -2.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.42 | Tolerated | 3.39 | 32 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||
| c.1435C>T | R479W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479W is not reported in ClinVar and is present in gnomAD (ID 6‑33438467‑C‑T). Functional prediction tools show a split opinion: benign calls come from REVEL, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic; Foldetta remains inconclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | 6-33438467-C-T | 6 | 3.72e-6 | -11.356 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 0.249 | Likely Benign | 0.1046 | 0.2933 | 0.60 | Ambiguous | 0.1 | 0.72 | Ambiguous | 0.66 | Ambiguous | 0.42 | Likely Benign | -4.75 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 3.39 | 32 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||
| c.1436G>A | R479Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R479Q is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (variant ID 6‑33438468‑G‑A). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 HumDiv and HumVar both predict a pathogenic impact. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as likely benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” status; thus the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Uncertain | 1 | 6-33438468-G-A | 7 | 4.34e-6 | -7.109 | In-Between | 0.259 | Likely Benign | Likely Benign | 0.191 | Likely Benign | 0.2448 | 0.1812 | 0.54 | Ambiguous | 0.1 | 0.57 | Ambiguous | 0.56 | Ambiguous | 0.49 | Likely Benign | -1.16 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.31 | Tolerated | 3.39 | 32 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||
| c.1436G>C | R479P 2D 3DClick to see structure in 3D Viewer AIClinVar lists the SynGAP1 R479P variant as Uncertain, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Those that predict a pathogenic effect are FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are AlphaMissense‑Optimized and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as pathogenic. Overall, the majority of tools and the high‑accuracy methods support a pathogenic classification, which is in contrast to the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | Uncertain | 1 | -11.795 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.277 | Likely Benign | 0.1993 | 0.3747 | 2.86 | Destabilizing | 0.2 | 3.88 | Destabilizing | 3.37 | Destabilizing | 0.81 | Ambiguous | -3.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.41 | Benign | 0.18 | Tolerated | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||
| c.1436G>T | R479L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R479L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized remains uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No single metric dominates, and the overall evidence is balanced. Therefore, the variant’s pathogenicity is inconclusive; it is not contradicted by ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.419256 | Uncertain | 0.820 | 0.249 | 0.000 | -11.118 | Likely Pathogenic | 0.832 | Likely Pathogenic | Ambiguous | 0.265 | Likely Benign | 0.1326 | 0.3624 | 0.45 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.29 | Likely Benign | 0.39 | Likely Benign | -4.21 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.15 | Tolerated | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1438G>A | E480K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480K is catalogued in gnomAD (ID 6‑33438470‑G‑A) but has no entry in ClinVar. Functional prediction tools cluster into two groups: benign predictions come from FoldX and SIFT, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results are reported by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E480K is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-A | 1 | 6.20e-7 | -14.059 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.768 | Likely Pathogenic | 0.1828 | 0.6813 | 0.40 | Likely Benign | 0.1 | 1.08 | Ambiguous | 0.74 | Ambiguous | 0.83 | Ambiguous | -3.45 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | -1.26 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||
| c.1438G>C | E480Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E480Q is not reported in ClinVar (no ClinVar ID) and is present in gnomAD (ID 6‑33438470‑G‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain and therefore not used as evidence. High‑accuracy assessments show Foldetta predicts benign stability change, SGM Consensus predicts pathogenic, and AlphaMissense‑Optimized is inconclusive. Overall, the predictions are split, but the presence of a benign prediction from a high‑accuracy folding method and the lack of a ClinVar pathogenic claim suggest the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-C | 2 | 1.24e-6 | -12.336 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.480 | Likely Benign | 0.0854 | 0.6870 | 0.43 | Likely Benign | 0.0 | -0.01 | Likely Benign | 0.21 | Likely Benign | 0.75 | Ambiguous | -2.29 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.29 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||
| c.1439A>C | E480A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only SIFT, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the four pathogenic‑predicted tools above) as likely pathogenic, and Foldetta as uncertain. Because most evidence points to a deleterious effect, the variant is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -13.192 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 0.694 | Likely Pathogenic | 0.3468 | 0.6635 | 0.91 | Ambiguous | 0.1 | 1.15 | Ambiguous | 1.03 | Ambiguous | 0.55 | Ambiguous | -5.04 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.25 | Pathogenic | 0.09 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1439A>G | E480G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480G missense variant is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify it as pathogenic. Predictions that are uncertain—FoldX, premPS, and AlphaMissense‑Optimized—do not provide evidence for benignity. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic, and AlphaMissense‑Optimized remains uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -11.651 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.778 | Likely Pathogenic | 0.2806 | 0.6172 | 1.83 | Ambiguous | 0.1 | 2.34 | Destabilizing | 2.09 | Destabilizing | 0.65 | Ambiguous | -5.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.03 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1439A>T | E480V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E480V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only premPS. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic or likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of predictions support a pathogenic effect for E480V. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -12.347 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.797 | Likely Pathogenic | 0.0496 | 0.7192 | 0.94 | Ambiguous | 0.1 | 0.74 | Ambiguous | 0.84 | Ambiguous | 0.31 | Likely Benign | -6.07 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | -1.24 | Pathogenic | 0.02 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1440G>C | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta remains uncertain. Overall, the balance of evidence favors a benign classification for E480D, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.405 | Likely Benign | 0.1526 | 0.4130 | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1440G>T | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta providing no definitive stability change. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.405 | Likely Benign | 0.1526 | 0.4130 | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||
| c.1441C>A | H481N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H481N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools—Rosetta and AlphaMissense‑Default—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.229 | Likely Pathogenic | 0.381 | Ambiguous | Likely Benign | 0.205 | Likely Benign | 0.1205 | 0.1631 | 0.16 | Likely Benign | 0.1 | 0.54 | Ambiguous | 0.35 | Likely Benign | 0.09 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.68 | Benign | 0.57 | Tolerated | 2 | 1 | -0.3 | -23.04 | ||||||||||||||||||||||||||
| c.1441C>G | H481D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H481D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic signal: the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Uncertain results from AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect for H481D, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -11.822 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | 0.273 | Likely Benign | 0.2109 | 0.1058 | -0.09 | Likely Benign | 0.1 | 0.54 | Ambiguous | 0.23 | Likely Benign | 0.70 | Ambiguous | -5.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.50 | Tolerated | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||
| c.1441C>T | H481Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H481Y is listed in ClinVar as benign (ClinVar ID 1543764.0) and is present in the gnomAD database (gnomAD ID 6‑33438473‑C‑T). Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta report uncertain stability effects. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Taking all available evidence together, the variant is most likely benign, which is consistent with its ClinVar benign annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | Likely Benign | 1 | 6-33438473-C-T | 16 | 9.91e-6 | -10.910 | Likely Pathogenic | 0.565 | Likely Pathogenic | Likely Benign | 0.256 | Likely Benign | 0.0610 | 0.3558 | -0.53 | Ambiguous | 0.1 | -0.46 | Likely Benign | -0.50 | Ambiguous | 0.20 | Likely Benign | -3.32 | Deleterious | 0.988 | Probably Damaging | 0.979 | Probably Damaging | 3.40 | Benign | 0.59 | Tolerated | 3.37 | 33 | 0 | 2 | 1.9 | 26.03 | 256.5 | -44.4 | 0.0 | 0.0 | 0.2 | 0.2 | X | X | Uncertain | The imidazole ring of the His481 side chain is located in a short helical structure (res. Glu480-Leu482) within an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. In the WT simulations, His481 alternately stacks against Arg485, Arg587, and Glu480 without a definite role. In the variant simulations, Tyr481 also alternately stacks with nearby arginine residues, including Arg485, Arg587, and Arg479. The interaction between Tyr481 and Arg479 affects the α-α loop, causing it to fold into a distorted helical structure, an effect that might be more pronounced during protein folding. Finally, the potential effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | ||||||||
| c.1442A>C | H481P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H481P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM. Those that predict a pathogenic effect comprise SGM Consensus (Likely Pathogenic), PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and PROVEAN. Tools with inconclusive results are Foldetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta remains uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -10.205 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 0.385 | Likely Benign | 0.1979 | 0.3553 | -0.48 | Likely Benign | 0.3 | 3.69 | Destabilizing | 1.61 | Ambiguous | 0.67 | Ambiguous | -5.84 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.26 | Tolerated | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||
| c.1442A>G | H481R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H481R is not listed in ClinVar and has no reported allele in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by AlphaMissense‑Optimized, premPS, and Rosetta. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -11.753 | Likely Pathogenic | 0.823 | Likely Pathogenic | Ambiguous | 0.252 | Likely Benign | 0.1515 | 0.1690 | -0.45 | Likely Benign | 0.1 | 0.68 | Ambiguous | 0.12 | Likely Benign | 0.59 | Ambiguous | -4.48 | Deleterious | 0.983 | Probably Damaging | 0.977 | Probably Damaging | 3.47 | Benign | 0.53 | Tolerated | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||
| c.1442A>T | H481L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H481L missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools (seven benign vs five pathogenic) lean toward a benign interpretation, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign, though a subset of high‑accuracy predictors suggest pathogenicity, indicating some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -9.097 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | 0.349 | Likely Benign | 0.0661 | 0.4678 | -0.58 | Ambiguous | 0.1 | 0.15 | Likely Benign | -0.22 | Likely Benign | 0.29 | Likely Benign | -5.91 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 3.41 | Benign | 0.48 | Tolerated | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||
| c.1443C>A | H481Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 H481Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the balance of evidence leans toward a benign effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.524 | Likely Pathogenic | 0.663 | Likely Pathogenic | Likely Benign | 0.243 | Likely Benign | 0.1052 | 0.2797 | -0.41 | Likely Benign | 0.1 | 0.31 | Likely Benign | -0.05 | Likely Benign | 0.32 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.55 | Benign | 0.51 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1443C>G | H481Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 H481Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the balance of evidence leans toward a benign effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.257454 | Structured | 0.430977 | Uncertain | 0.764 | 0.247 | 0.000 | -8.524 | Likely Pathogenic | 0.663 | Likely Pathogenic | Likely Benign | 0.243 | Likely Benign | 0.1052 | 0.2797 | -0.41 | Likely Benign | 0.1 | 0.31 | Likely Benign | -0.05 | Likely Benign | 0.32 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.55 | Benign | 0.51 | Tolerated | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||
| c.1444C>A | L482I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from PROVEAN and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (REVEL, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate pathogenicity. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments give a consistent picture: AlphaMissense‑Optimized predicts a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain outcome. Overall, the preponderance of pathogenic predictions suggests that the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.116 | Likely Pathogenic | 0.760 | Likely Pathogenic | Likely Benign | 0.600 | Likely Pathogenic | 0.0677 | 0.2368 | 1.29 | Ambiguous | 0.1 | 1.90 | Ambiguous | 1.60 | Ambiguous | 0.71 | Ambiguous | -1.97 | Neutral | 0.994 | Probably Damaging | 0.994 | Probably Damaging | -1.31 | Pathogenic | 0.05 | Affected | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||
| c.1444C>G | L482V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482V has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.676 | Likely Pathogenic | 0.734 | Likely Pathogenic | Likely Benign | 0.709 | Likely Pathogenic | 0.1074 | 0.2027 | 1.97 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.75 | Ambiguous | 0.76 | Ambiguous | -2.95 | Deleterious | 0.989 | Probably Damaging | 0.984 | Probably Damaging | -1.30 | Pathogenic | 0.10 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1444C>T | L482F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX and premPS, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as Uncertain, SGM Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L482F. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.257 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.724 | Likely Pathogenic | 0.0457 | 0.1814 | 0.48 | Likely Benign | 0.0 | 1.09 | Ambiguous | 0.79 | Ambiguous | 0.43 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | -1.22 | Pathogenic | 0.01 | Affected | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||
| c.1445T>A | L482H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482H is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are absent; all available pathogenic predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus vote (Likely Pathogenic) uniformly indicate a deleterious impact. Uncertain predictions come from FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. No evidence suggests a benign outcome. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic predictions, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -13.825 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.886 | Likely Pathogenic | 0.1000 | 0.0879 | 1.49 | Ambiguous | 0.0 | 1.44 | Ambiguous | 1.47 | Ambiguous | 1.64 | Destabilizing | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.28 | Pathogenic | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| c.1445T>C | L482P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482P is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -12.866 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.896 | Likely Pathogenic | 0.2756 | 0.0825 | 3.59 | Destabilizing | 0.1 | 10.87 | Destabilizing | 7.23 | Destabilizing | 1.55 | Destabilizing | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.01 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1445T>G | L482R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while FoldX, Rosetta, and Foldetta return uncertain results. In a consensus framework, the SGM‑Consensus score is “Likely Pathogenic,” reflecting the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus is Likely Pathogenic, and Foldetta remains inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -14.684 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.878 | Likely Pathogenic | 0.1255 | 0.0679 | 0.74 | Ambiguous | 0.1 | 1.31 | Ambiguous | 1.03 | Ambiguous | 1.53 | Destabilizing | -5.92 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | -1.27 | Pathogenic | 0.01 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1447A>C | I483L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact, and premPS remains uncertain. High‑accuracy assessments are uniformly benign: AlphaMissense‑Optimized is benign, the SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Taken together, the majority of evidence, including the high‑accuracy tools, supports a benign classification for I483L. This conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.258 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 0.341 | Likely Benign | 0.0664 | 0.2461 | 0.31 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.67 | Ambiguous | -1.86 | Neutral | 0.879 | Possibly Damaging | 0.970 | Probably Damaging | 4.09 | Benign | 0.31 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||
| c.1447A>G | I483V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions are reported by premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Predictions marked as uncertain include FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, whereas Foldetta remains uncertain. Overall, the balance of evidence from both general and high‑accuracy tools leans toward a benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | Conflicting | 2 | -10.121 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 0.228 | Likely Benign | 0.0876 | 0.2691 | 1.00 | Ambiguous | 0.0 | 0.27 | Likely Benign | 0.64 | Ambiguous | 1.02 | Destabilizing | -0.86 | Neutral | 0.914 | Possibly Damaging | 0.921 | Probably Damaging | 3.23 | Benign | 0.03 | Affected | 3.37 | 32 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||||
| c.1447A>T | I483L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” In contrast, polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic impact, and premPS remains uncertain. High‑accuracy assessments are uniformly benign: AlphaMissense‑Optimized is benign, the SGM‑Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Taken together, the majority of evidence, including the high‑accuracy tools, supports a benign classification for I483L. This conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.258 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 0.342 | Likely Benign | 0.0664 | 0.2461 | 0.31 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.67 | Ambiguous | -1.86 | Neutral | 0.879 | Possibly Damaging | 0.970 | Probably Damaging | 4.09 | Benign | 0.31 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||
| c.1448T>A | I483K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -18.260 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.585 | Likely Pathogenic | 0.0868 | 0.0670 | 3.53 | Destabilizing | 0.1 | 5.15 | Destabilizing | 4.34 | Destabilizing | 2.01 | Destabilizing | -6.50 | Deleterious | 0.962 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||
| c.1448T>C | I483T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.692 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.474 | Likely Benign | 0.0888 | 0.0840 | 2.32 | Destabilizing | 0.0 | 2.05 | Destabilizing | 2.19 | Destabilizing | 1.77 | Destabilizing | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.15 | Benign | 0.05 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.1448T>G | I483R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -17.066 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.595 | Likely Pathogenic | 0.1120 | 0.0870 | 5.14 | Destabilizing | 0.4 | 4.09 | Destabilizing | 4.62 | Destabilizing | 1.97 | Destabilizing | -6.50 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | -2 | -3 | -9.0 | 43.03 | |||||||||||||||||||||||||
| c.1449A>G | I483M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I483M missense variant is not reported in ClinVar (ClinVar status: not present) but is catalogued in gnomAD (gnomAD ID: 6‑33438481‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as benign. No conclusive folding‑stability result is available from Rosetta. Overall, the majority of high‑accuracy tools (two benign, one pathogenic) lean toward a benign interpretation, and this assessment is not contradicted by any ClinVar annotation. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | 6-33438481-A-G | 1 | 6.20e-7 | -8.839 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | 0.261 | Likely Benign | 0.0607 | 0.1959 | 0.02 | Likely Benign | 0.0 | 0.73 | Ambiguous | 0.38 | Likely Benign | 1.06 | Destabilizing | -2.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.05 | Affected | 3.37 | 32 | 1 | 2 | -2.6 | 18.03 | ||||||||||||||||||||
| c.145T>A | C49S 2D AIThe SynGAP1 missense variant C49S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs. 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard predictors lean toward pathogenicity, but the high‑accuracy tools do not provide definitive support. Thus, the variant is most likely pathogenic based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.575 | Likely Benign | 0.704 | Likely Pathogenic | Likely Benign | 0.260 | Likely Benign | 0.3855 | 0.1686 | -3.07 | Deleterious | 0.462 | Possibly Damaging | 0.478 | Possibly Damaging | 3.91 | Benign | 0.00 | Affected | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||
| c.145T>C | C49R 2D AIThe SynGAP1 missense variant C49R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain and no Foldetta (FoldX‑MD/Rosetta) result is available. Taken together, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -10.000 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.320 | Likely Benign | 0.1605 | 0.2120 | -3.53 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||||||||
| c.145T>G | C49G 2D AIThe SynGAP1 missense variant C49G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic versus four benign) lean toward a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.464 | Likely Benign | 0.674 | Likely Pathogenic | Likely Benign | 0.351 | Likely Benign | 0.2419 | 0.2528 | -3.64 | Deleterious | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.87 | Benign | 0.00 | Affected | -3 | -3 | -2.9 | -46.09 | ||||||||||||||||||||||||||||||||||||
| c.146G>A | C49Y 2D AIThe SynGAP1 missense variant C49Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is classified as Likely Pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for C49Y. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -11.097 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.312 | Likely Benign | 0.1016 | 0.3172 | -3.38 | Deleterious | 0.676 | Possibly Damaging | 0.761 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||||||||
| c.146G>C | C49S 2D AIThe SynGAP1 missense variant C49S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of conventional tools (five pathogenic vs four benign) lean toward a pathogenic interpretation, but the single high‑accuracy benign prediction and the inconclusive SGM Consensus leave the assessment uncertain. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -6.575 | Likely Benign | 0.704 | Likely Pathogenic | Likely Benign | 0.224 | Likely Benign | 0.3855 | 0.1686 | -3.07 | Deleterious | 0.462 | Possibly Damaging | 0.478 | Possibly Damaging | 3.91 | Benign | 0.00 | Affected | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||||||||||
| c.146G>T | C49F 2D AIThe SynGAP1 missense variant C49F is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect are REVEL and FATHMM, while a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—classifies the variant as pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -7.194 | In-Between | 0.893 | Likely Pathogenic | Ambiguous | 0.301 | Likely Benign | 0.1199 | 0.3690 | -3.21 | Deleterious | 0.676 | Possibly Damaging | 0.695 | Possibly Damaging | 3.86 | Benign | 0.00 | Affected | -4 | -2 | 0.3 | 44.04 | ||||||||||||||||||||||||||||||||||||
| c.1474A>C | K492Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.685 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.463 | Likely Benign | 0.3534 | 0.0830 | 0.34 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.64 | Ambiguous | 1.13 | Destabilizing | -3.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.02 | Affected | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||
| c.1474A>G | K492E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. The remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which contradicts its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | Conflicting | 2 | -16.175 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.510 | Likely Pathogenic | 0.2968 | 0.0650 | 1.53 | Ambiguous | 0.1 | 1.90 | Ambiguous | 1.72 | Ambiguous | 1.42 | Destabilizing | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.99 | Benign | 0.01 | Affected | 3.37 | 35 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||
| c.1475A>C | K492T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the majority—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized—predict a pathogenic impact. Four methods (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy predictors give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta remains uncertain. Overall, the evidence strongly favors a pathogenic classification, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -16.126 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.595 | Likely Pathogenic | 0.1691 | 0.2825 | 1.09 | Ambiguous | 0.1 | 0.88 | Ambiguous | 0.99 | Ambiguous | 0.98 | Ambiguous | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.96 | Benign | 0.04 | Affected | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1475A>G | K492R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (seven pathogenic vs. six benign) lean toward a pathogenic interpretation, and this does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -11.290 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | 0.487 | Likely Benign | 0.3911 | 0.0835 | -0.20 | Likely Benign | 0.1 | 0.45 | Likely Benign | 0.13 | Likely Benign | 0.84 | Ambiguous | -2.98 | Deleterious | 0.997 | Probably Damaging | 0.990 | Probably Damaging | 3.25 | Benign | 0.05 | Affected | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.1475A>T | K492I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492I is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions from premPS and FATHMM; pathogenic predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results come from FoldX, Rosetta, and Foldetta. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic (3/4 votes). Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -18.661 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.645 | Likely Pathogenic | 0.0875 | 0.2810 | -0.54 | Ambiguous | 0.1 | -0.59 | Ambiguous | -0.57 | Ambiguous | 0.49 | Likely Benign | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.94 | Benign | 0.00 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.1476A>C | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.512 | Likely Pathogenic | 0.2814 | 0.0926 | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1476A>T | K492N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K492N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No folding‑stability predictions are definitive. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.048 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.512 | Likely Pathogenic | 0.2814 | 0.0926 | 0.92 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.01 | Ambiguous | 1.25 | Destabilizing | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.92 | Benign | 0.00 | Affected | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1477G>A | A493T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A493T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors indicates a deleterious effect: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, premPS, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as pathogenic or likely pathogenic. Only Rosetta predicts a benign outcome; FoldX, Foldetta, and AlphaMissense‑Optimized are uncertain or unavailable. High‑accuracy tools give the following: AlphaMissense‑Optimized – uncertain; SGM Consensus – likely pathogenic; Foldetta – uncertain. Taken together, the preponderance of evidence supports a pathogenic effect for A493T. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -10.366 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.727 | Likely Pathogenic | 0.0964 | 0.3972 | 0.82 | Ambiguous | 0.0 | 0.39 | Likely Benign | 0.61 | Ambiguous | 1.10 | Destabilizing | -3.41 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.04 | Affected | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1477G>C | A493P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict deleterious effects. No tool in the dataset indicates a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -15.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.883 | Likely Pathogenic | 0.1490 | 0.2907 | 4.96 | Destabilizing | 0.1 | 10.79 | Destabilizing | 7.88 | Destabilizing | 1.32 | Destabilizing | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.02 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1477G>T | A493S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as unavailable. Based on the consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -6.271 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.507 | Likely Pathogenic | 0.1821 | 0.2763 | 0.66 | Ambiguous | 0.1 | 1.10 | Ambiguous | 0.88 | Ambiguous | 0.53 | Ambiguous | -2.12 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.27 | Pathogenic | 0.44 | Tolerated | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||
| c.1478C>A | A493D 2D AISynGAP1 missense variant A493D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -16.834 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.925 | Likely Pathogenic | 0.1437 | 0.1541 | 4.45 | Destabilizing | 1.5 | 3.59 | Destabilizing | 4.02 | Destabilizing | 1.60 | Destabilizing | -5.25 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.1478C>G | A493G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A493G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus all predict pathogenicity, while only AlphaMissense‑Optimized predicts a benign outcome. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains pathogenic; Foldetta likewise yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for A493G, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -11.379 | Likely Pathogenic | 0.571 | Likely Pathogenic | Likely Benign | 0.764 | Likely Pathogenic | 0.1673 | 0.2228 | 1.85 | Ambiguous | 0.0 | 1.63 | Ambiguous | 1.74 | Ambiguous | 1.40 | Destabilizing | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.40 | Pathogenic | 0.02 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1478C>T | A493V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A493V missense variant has no ClinVar entry and is reported in gnomAD (6‑33438510‑C‑T). Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Benign predictions are limited to SIFT and Foldetta. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus indicates likely pathogenic, and Foldetta predicts benign stability. No other tools provide conclusive evidence. Overall, the preponderance of pathogenic predictions, including the consensus and multiple independent algorithms, suggests the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | 6-33438510-C-T | 3 | 1.86e-6 | -12.511 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.735 | Likely Pathogenic | 0.0877 | 0.3860 | 0.56 | Ambiguous | 0.1 | -0.67 | Ambiguous | -0.06 | Likely Benign | 0.91 | Ambiguous | -3.84 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.31 | Pathogenic | 0.10 | Tolerated | 3.37 | 35 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||
| c.147C>G | C49W 2D AIThe SynGAP1 missense variant C49W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic and the SGM‑Consensus is “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that C49W is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.209395 | Structured | 0.445316 | Uncertain | 0.541 | 0.704 | 0.000 | -12.247 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.291 | Likely Benign | 0.1380 | 0.3172 | -3.56 | Deleterious | 0.880 | Possibly Damaging | 0.914 | Probably Damaging | 3.83 | Benign | 0.00 | Affected | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||||||||
| c.1480A>C | I494L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence (five pathogenic versus four benign predictions, with several uncertain calls) leans toward a pathogenic interpretation. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.175 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.513 | Likely Pathogenic | 0.0816 | 0.2851 | 0.28 | Likely Benign | 0.1 | 1.11 | Ambiguous | 0.70 | Ambiguous | 0.91 | Ambiguous | -1.69 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -0.88 | Pathogenic | 0.11 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1480A>G | I494V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I494V is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438512‑A‑G). Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Pathogenic predictions come from premPS and FATHMM. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign; Foldetta remains uncertain. Overall, the majority of evidence supports a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | Conflicting | 2 | 6-33438512-A-G | 36 | 2.23e-5 | -7.102 | In-Between | 0.112 | Likely Benign | Likely Benign | 0.439 | Likely Benign | 0.0965 | 0.2491 | 1.16 | Ambiguous | 0.0 | 0.71 | Ambiguous | 0.94 | Ambiguous | 1.02 | Destabilizing | -0.83 | Neutral | 0.278 | Benign | 0.179 | Benign | -1.30 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 4 | 3 | -0.3 | -14.03 | 248.6 | 29.3 | 0.0 | 0.0 | -1.1 | 0.5 | X | Potentially Benign | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the hydrophobic iso-propyl side chain of Val494, which is of a similar size and has similar physicochemical properties to Ile494 in the WT, resides similarly in the inter-helix hydrophobic space. Thus, no negative effects on the protein structure are observed. | ||||||||||
| c.1480A>T | I494L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta indicating uncertain stability change. Overall, the balance of evidence leans toward pathogenicity, with a majority of tools and the SGM Consensus supporting a deleterious effect. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.175 | Likely Pathogenic | 0.478 | Ambiguous | Likely Benign | 0.513 | Likely Pathogenic | 0.0816 | 0.2851 | 0.28 | Likely Benign | 0.1 | 1.11 | Ambiguous | 0.70 | Ambiguous | 0.91 | Ambiguous | -1.69 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -0.88 | Pathogenic | 0.11 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1481T>A | I494K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I494K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -15.950 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.925 | Likely Pathogenic | 0.1015 | 0.0870 | 4.23 | Destabilizing | 0.2 | 5.33 | Destabilizing | 4.78 | Destabilizing | 1.89 | Destabilizing | -6.40 | Deleterious | 0.987 | Probably Damaging | 0.937 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||
| c.1481T>C | I494T 2D AIThe SynGAP1 missense variant I494T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.033 | Likely Pathogenic | 0.754 | Likely Pathogenic | Likely Benign | 0.907 | Likely Pathogenic | 0.1003 | 0.0640 | 2.45 | Destabilizing | 0.7 | 2.12 | Destabilizing | 2.29 | Destabilizing | 1.73 | Destabilizing | -4.61 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.38 | Pathogenic | 0.01 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.1481T>G | I494R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I494R is listed in ClinVar as Pathogenic (ClinVar ID 1685460.0) and is not reported in gnomAD. Prediction tools that assess functional impact all converge on a pathogenic outcome: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | Likely Pathogenic | 1 | -15.758 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.911 | Likely Pathogenic | 0.1180 | 0.0870 | 6.71 | Destabilizing | 0.3 | 3.40 | Destabilizing | 5.06 | Destabilizing | 2.19 | Destabilizing | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.957 | Probably Damaging | -1.41 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -2 | -3 | -9.0 | 43.03 | 273.9 | -59.8 | 0.0 | 0.0 | 0.0 | 0.1 | X | X | X | X | Potentially Pathogenic | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the bulkier and positively charged residue, Arg494, weakens the integrity of the opposing helix. Additionally, the bulkier Arg494 stacks with Phe484, causing the α-helices to move farther apart to accommodate it. This mutation could have substantial negative effects due to the fundamental role of hydrophobic packing, which is disrupted by Arg494 during protein folding. | |||||||||
| c.1482A>G | I494M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I494M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence leans toward pathogenicity, with a majority of tools predicting a deleterious effect. This conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -8.223 | Likely Pathogenic | 0.356 | Ambiguous | Likely Benign | 0.542 | Likely Pathogenic | 0.0676 | 0.1789 | 0.35 | Likely Benign | 0.2 | 1.98 | Ambiguous | 1.17 | Ambiguous | 0.98 | Ambiguous | -2.25 | Neutral | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.15 | Pathogenic | 0.23 | Tolerated | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||
| c.1483G>A | E495K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results (Rosetta and premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also as pathogenic, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for E495K, which is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | -11.478 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.1974 | 0.5039 | 0.15 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.41 | Likely Benign | 0.70 | Ambiguous | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||
| c.1483G>C | E495Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495Q missense variant is not listed in ClinVar and has no reported allele in gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta, all of which score the substitution as benign. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts benign stability. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -11.050 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 0.748 | Likely Pathogenic | 0.1093 | 0.4973 | -0.27 | Likely Benign | 0.1 | 0.11 | Likely Benign | -0.08 | Likely Benign | 0.89 | Ambiguous | -2.92 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1484A>C | E495A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include FoldX, while the remaining evaluated algorithms (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. No contradictory evidence is present from ClinVar or population databases. Overall, the preponderance of predictions supports a pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -9.229 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.834 | Likely Pathogenic | 0.2711 | 0.4259 | 0.42 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.69 | Ambiguous | -5.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.38 | Pathogenic | 0.01 | Affected | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1484A>G | E495G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495G missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438516‑A‑G). Among the available in‑silico predictors, the following tools uniformly indicate a pathogenic effect: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which itself is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). No tool in the dataset predicts a benign outcome; predictions that are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” and Foldetta as “Uncertain.” Overall, the preponderance of pathogenic predictions strongly suggests that the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | 6-33438516-A-G | 1 | 6.20e-7 | -9.400 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 0.867 | Likely Pathogenic | 0.2177 | 0.4784 | 1.21 | Ambiguous | 0.0 | 2.06 | Destabilizing | 1.64 | Ambiguous | 0.78 | Ambiguous | -6.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.46 | Pathogenic | 0.02 | Affected | 3.37 | 35 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||
| c.1484A>T | E495V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence (10 pathogenic‑predicted tools versus 4 benign) indicates that E495V is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -12.031 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.887 | Likely Pathogenic | 0.0646 | 0.5457 | 0.43 | Likely Benign | 0.2 | -0.32 | Likely Benign | 0.06 | Likely Benign | 0.47 | Likely Benign | -6.83 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1485A>C | E495D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E495D is listed in ClinVar with an uncertain significance (ClinVar ID 2000233.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from SIFT and ESM1b, and pathogenic predictions from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN classifies the variant as likely pathogenic. AlphaMissense‑Optimized also predicts pathogenicity, whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of deleterious impact. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Conflicting | 2 | -3.574 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.566 | Likely Pathogenic | 0.1778 | 0.3064 | 1.39 | Ambiguous | 0.1 | 1.03 | Ambiguous | 1.21 | Ambiguous | 0.98 | Ambiguous | -2.52 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 3 | 2 | 0.0 | -14.03 | 220.6 | 38.8 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | Uncertain | Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1485A>T | E495D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495D is not reported in ClinVar (status: None) and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from SIFT and ESM1b, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta provides no definitive stability change. Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -3.574 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.566 | Likely Pathogenic | 0.1778 | 0.3064 | 1.39 | Ambiguous | 0.1 | 1.03 | Ambiguous | 1.21 | Ambiguous | 0.98 | Ambiguous | -2.52 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 3.37 | 35 | 3 | 2 | 0.0 | -14.03 | 220.6 | 38.8 | 0.0 | 0.0 | 0.1 | 0.1 | X | X | Uncertain | Glu495 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighboring Lys492 and with Arg596 on an opposing α-helix (res. Glu582-Met603) in the WT simulations. In the variant simulations, the acidic carboxylate side chain of Asp495 can also form salt bridges with both Lys492 and Arg596. However, the shorter side chain of aspartate tends to favor forming a salt bridge with the nearby Arg499 on the same α-helix instead. Asp495 might not maintain the salt bridge with Arg596 on the opposing α-helix as efficiently as Glu495 in the WT, potentially weakening the tertiary structure. Regardless, the potential negative effect is likely to be minor, with no deleterious effects observed on the protein structure during the simulations. However, due to its location at the GAP-Ras interface, the effect of the residue swap on SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||||
| c.1486G>A | E496K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E496K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FoldX, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. Uncertain predictions come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the evidence strongly favors a pathogenic classification for E496K, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -15.795 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.743 | Likely Pathogenic | 0.1810 | 0.3528 | 0.38 | Likely Benign | 0.1 | 1.77 | Ambiguous | 1.08 | Ambiguous | 0.76 | Ambiguous | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.40 | Pathogenic | 0.04 | Affected | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1486G>C | E496Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E496Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). In silico predictors that classify the variant as benign include FoldX, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized, whereas those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta is inconclusive. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized indicates a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign impact. Overall, the majority of predictions (8 pathogenic vs. 5 benign) and the consensus of high‑accuracy methods lean toward a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -11.868 | Likely Pathogenic | 0.651 | Likely Pathogenic | Likely Benign | 0.586 | Likely Pathogenic | 0.0884 | 0.3262 | 0.13 | Likely Benign | 0.1 | 0.61 | Ambiguous | 0.37 | Likely Benign | 0.50 | Likely Benign | -2.68 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.15 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1487A>C | E496A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496A missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX is uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the majority of predictions (8 pathogenic vs. 5 benign) indicate a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -11.159 | Likely Pathogenic | 0.598 | Likely Pathogenic | Likely Benign | 0.681 | Likely Pathogenic | 0.2806 | 0.3548 | 0.68 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.46 | Likely Benign | 0.47 | Likely Benign | -4.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.41 | Pathogenic | 0.09 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1487A>G | E496G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496G missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: no tool predicts a benign outcome, while eight tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the preponderance of evidence points to a pathogenic effect, contradicting the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | Uncertain | 1 | -13.529 | Likely Pathogenic | 0.850 | Likely Pathogenic | Ambiguous | 0.825 | Likely Pathogenic | 0.2435 | 0.3473 | 1.83 | Ambiguous | 0.1 | 1.76 | Ambiguous | 1.80 | Ambiguous | 0.92 | Ambiguous | -6.16 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.02 | Affected | 3.37 | 35 | 0 | -2 | 3.1 | -72.06 | 173.9 | 103.1 | 0.0 | 0.0 | -0.7 | 0.0 | X | X | Potentially Pathogenic | Glu496 is located in the α-helix (res. Leu489-Glu519), and its carboxylate group forms salt bridges with the neighbouring residues Lys492 and Arg499 in the WT simulations. Glu496 also forms a hydrogen bond with Ser449 on an opposing helix (res. Val441-Ser457). In the variant simulations, Gly496 cannot form these salt bridges, which could weaken the secondary structure. Additionally, the loss of the hydrogen bond with Ser449 on the opposite helix can weaken the tertiary structure assembly. Moreover, glycine is an α-helix breaker, and it is seen to weaken the integrity of the helix as the hydrogen bonding between the backbone atoms of Gly496 and Ala493 breaks down. Also, due to its location at the GAP-Ras interface, the interaction of Glu496 with Arg499 and Lys492 might play a role in complex association and stability, which cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1487A>T | E496V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E496V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Foldetta, and premPS, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is Uncertain; SGM‑Consensus remains Likely Pathogenic; Foldetta, a folding‑stability predictor that integrates FoldX‑MD and Rosetta outputs, classifies the variant as Benign. Because the variant is not present in ClinVar, there is no clinical annotation to contradict the computational evidence. Overall, the preponderance of pathogenic predictions, including the consensus score, suggests that E496V is most likely pathogenic, though the conflicting high‑accuracy folding stability result indicates uncertainty that warrants further functional validation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -14.290 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 0.823 | Likely Pathogenic | 0.0556 | 0.3746 | 0.17 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.25 | Likely Benign | 0.26 | Likely Benign | -6.16 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.43 | Pathogenic | 0.02 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1488G>C | E496D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E496D missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain predictions come from Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | -10.552 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.583 | Likely Pathogenic | 0.1576 | 0.1912 | 0.43 | Likely Benign | 0.2 | 1.78 | Ambiguous | 1.11 | Ambiguous | 1.18 | Destabilizing | -2.78 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.45 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||
| c.1488G>T | E496D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E496D is reported in gnomAD (ID 6‑33438520‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions are provided only by FoldX, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—classify the change as pathogenic. Uncertain results come from Rosetta, Foldetta, and AlphaMissense‑Optimized and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.383296 | Uncertain | 0.945 | 0.179 | 0.000 | 6-33438520-G-T | 2 | 1.24e-6 | -10.552 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.583 | Likely Pathogenic | 0.1576 | 0.1912 | 0.43 | Likely Benign | 0.2 | 1.78 | Ambiguous | 1.11 | Ambiguous | 1.18 | Destabilizing | -2.78 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | -1.45 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||
| c.1489T>A | Y497N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on these concordant predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -11.884 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.870 | Likely Pathogenic | 0.2114 | 0.0612 | 3.64 | Destabilizing | 0.1 | 3.97 | Destabilizing | 3.81 | Destabilizing | 2.49 | Destabilizing | -8.85 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.66 | Pathogenic | 0.01 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.1489T>C | Y497H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -10.970 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.819 | Likely Pathogenic | 0.1983 | 0.0612 | 2.46 | Destabilizing | 0.1 | 2.40 | Destabilizing | 2.43 | Destabilizing | 1.29 | Destabilizing | -4.94 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.65 | Pathogenic | 0.02 | Affected | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||
| c.1489T>G | Y497D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. All available predictions are concordant and indicate a likely pathogenic impact. Thus, based on the collective computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -12.128 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.918 | Likely Pathogenic | 0.3621 | 0.0612 | 4.70 | Destabilizing | 0.2 | 4.29 | Destabilizing | 4.50 | Destabilizing | 2.36 | Destabilizing | -9.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.67 | Pathogenic | 0.01 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.148A>C | I50L 2D AIThe SynGAP1 missense variant I50L is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -3.509 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.0749 | 0.3247 | -0.73 | Neutral | 0.010 | Benign | 0.004 | Benign | 3.91 | Benign | 0.00 | Affected | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.148A>G | I50V 2D AIThe SynGAP1 missense variant I50V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus methods also support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence indicates that I50V is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -1.051 | Likely Benign | 0.141 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 0.1091 | 0.3159 | -0.24 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.18 | Benign | 0.00 | Affected | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.148A>T | I50F 2D AIThe SynGAP1 missense variant I50F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for I50F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -5.631 | Likely Benign | 0.681 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | 0.0483 | 0.2560 | -1.27 | Neutral | 0.334 | Benign | 0.074 | Benign | 3.75 | Benign | 0.00 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.1490A>C | Y497S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497S is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized) classifies the change as pathogenic, leaving no benign predictions. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a destabilizing, pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar annotation, the variant is most likely pathogenic, with no contradictory ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -13.171 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.814 | Likely Pathogenic | 0.3770 | 0.1419 | 3.65 | Destabilizing | 0.1 | 4.68 | Destabilizing | 4.17 | Destabilizing | 2.22 | Destabilizing | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.64 | Pathogenic | 0.03 | Affected | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.1490A>G | Y497C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497C is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all return a deleterious signal: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenic. No tool reports a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM Consensus as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as “Pathogenic.” Overall, the variant is most likely pathogenic based on the consensus of predictive algorithms, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | Uncertain | 1 | -11.872 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.806 | Likely Pathogenic | 0.2905 | 0.1488 | 3.88 | Destabilizing | 0.1 | 4.76 | Destabilizing | 4.32 | Destabilizing | 1.40 | Destabilizing | -8.82 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.65 | Pathogenic | 0.03 | Affected | 3.37 | 35 | 0 | -2 | 3.8 | -60.04 | 209.9 | 59.1 | -0.1 | 0.0 | -0.3 | 0.1 | X | X | Potentially Pathogenic | Tyr497 is located in the α-helix (res. Leu489-Glu519) within the inter-helix space of four α-helices (res. Leu489-Ile501, res. Val441-Ser457, res. Arg563-Glu578, res. Ala461-Val473). In the WT simulations, the phenol ring of Tyr497 hydrophobically packs with other residues in the inter-helix space (e.g., Leu465, Leu565, Val568). The hydroxyl group of Tyr497 also alternately forms hydrogen bonds with the carboxylate side chain of Gln456 and the backbone carbonyl of Glu564. Thus, Tyr497 plays a role in the folding and maintenance of the tertiary structure assembly between these four helices.In the variant simulations, the comparatively smaller residue, Cys497, cannot maintain any of the interactions seen with Tyr497 in the WT. Although no severe deleterious consequences are observed in the simulations, the structural effects could be more pronounced during actual protein folding. Indeed, the tertiary structure is seen to slightly break apart in the variant simulations. | |||||||||||
| c.1490A>T | Y497F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497F is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, ESM1b, and FATHMM; premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign based on the current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -8.566 | Likely Pathogenic | 0.199 | Likely Benign | Likely Benign | 0.578 | Likely Pathogenic | 0.2074 | 0.2242 | -0.27 | Likely Benign | 0.1 | 0.47 | Likely Benign | 0.10 | Likely Benign | 0.61 | Ambiguous | -3.75 | Deleterious | 0.367 | Benign | 0.131 | Benign | -1.15 | Pathogenic | 0.19 | Tolerated | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||
| c.1492A>C | M498L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | 2.556 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.271 | Likely Benign | 0.1319 | 0.3551 | -0.23 | Likely Benign | 0.1 | -0.89 | Ambiguous | -0.56 | Ambiguous | -0.53 | Ambiguous | 0.62 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.24 | Pathogenic | 0.92 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1492A>G | M498V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M498V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, Foldetta, premPS, polyPhen‑2 HumDiv, SIFT, FATHMM). Rosetta is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta predicts a pathogenic effect on protein stability. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -3.229 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 0.483 | Likely Benign | 0.2737 | 0.2737 | 2.74 | Destabilizing | 0.1 | 1.26 | Ambiguous | 2.00 | Destabilizing | 1.17 | Destabilizing | -1.82 | Neutral | 0.752 | Possibly Damaging | 0.279 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||
| c.1492A>T | M498L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only FATHMM predicts a pathogenic outcome, while Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | 2.556 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.271 | Likely Benign | 0.1319 | 0.3551 | -0.23 | Likely Benign | 0.1 | -0.89 | Ambiguous | -0.56 | Ambiguous | -0.53 | Ambiguous | 0.62 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.24 | Pathogenic | 0.92 | Tolerated | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||
| c.1493T>A | M498K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign calls come only from polyPhen‑2 HumDiv and HumVar, whereas the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict pathogenicity. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of evidence indicates that M498K is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -11.622 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.867 | Likely Pathogenic | 0.1281 | 0.0656 | 2.82 | Destabilizing | 0.1 | 2.86 | Destabilizing | 2.84 | Destabilizing | 1.79 | Destabilizing | -4.53 | Deleterious | 0.287 | Benign | 0.120 | Benign | -1.37 | Pathogenic | 0.00 | Affected | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||
| c.1493T>C | M498T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: all but one (polyPhen‑2 HumVar) predict pathogenicity, while polyPhen‑2 HumVar alone predicts benign. Uncertain predictions (ESM1b and AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy methods reinforce the pathogenic view: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. AlphaMissense‑Optimized remains inconclusive. Overall, the preponderance of evidence indicates that M498T is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -7.477 | In-Between | 0.869 | Likely Pathogenic | Ambiguous | 0.672 | Likely Pathogenic | 0.1925 | 0.1630 | 2.46 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.54 | Destabilizing | 1.41 | Destabilizing | -3.80 | Deleterious | 0.803 | Possibly Damaging | 0.343 | Benign | -1.19 | Pathogenic | 0.02 | Affected | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||
| c.1493T>G | M498R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498R is listed in ClinVar as Pathogenic (ClinVar ID 3907767.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only polyPhen‑2 HumVar; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions or stability results are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | Likely Pathogenic | 1 | -8.812 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.869 | Likely Pathogenic | 0.1482 | 0.0757 | 3.85 | Destabilizing | 0.2 | 2.35 | Destabilizing | 3.10 | Destabilizing | 1.76 | Destabilizing | -4.53 | Deleterious | 0.464 | Possibly Damaging | 0.120 | Benign | -1.36 | Pathogenic | 0.00 | Affected | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||
| c.1494G>A | M498I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 0.418 | Likely Benign | 0.1184 | 0.2537 | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1494G>C | M498I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 0.418 | Likely Benign | 0.1184 | 0.2537 | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1494G>T | M498I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 0.414 | Likely Benign | 0.1184 | 0.2537 | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||
| c.1495A>G | R499G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499G is listed in gnomAD (variant ID 6‑33438527‑A‑G) but has no ClinVar entry. Prediction tools that assess the variant’s effect on protein function overwhelmingly indicate a deleterious outcome: REVEL, FoldX‑MD (Rosetta component), Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as pathogenic. Only FoldX (overall) and AlphaMissense‑Optimized report uncertain results, which are treated as unavailable evidence. No tool predicts a benign effect. High‑accuracy assessments specifically show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. Taken together, the preponderance of evidence supports a pathogenic classification for R499G, and this conclusion is not contradicted by any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438527-A-G | 3 | 1.86e-6 | -9.960 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 0.681 | Likely Pathogenic | 0.2888 | 0.1798 | 1.55 | Ambiguous | 0.1 | 2.75 | Destabilizing | 2.15 | Destabilizing | 1.41 | Destabilizing | -4.50 | Deleterious | 0.958 | Probably Damaging | 0.769 | Possibly Damaging | -1.47 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||
| c.1496G>A | R499K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no evidence for either direction. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign prediction; Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect for R499K, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 4.366 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.248 | Likely Benign | 0.3531 | 0.1881 | 1.37 | Ambiguous | 0.1 | 0.53 | Ambiguous | 0.95 | Ambiguous | -0.77 | Ambiguous | 1.94 | Neutral | 0.001 | Benign | 0.008 | Benign | -1.03 | Pathogenic | 1.00 | Tolerated | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||
| c.1496G>C | R499T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and ESM1b, whereas a majority of tools (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic, AlphaMissense‑Optimized is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No evidence from ClinVar contradicts these predictions. Overall, the preponderance of computational evidence points to a pathogenic effect for R499T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -6.797 | Likely Benign | 0.855 | Likely Pathogenic | Ambiguous | 0.664 | Likely Pathogenic | 0.1732 | 0.2074 | 2.47 | Destabilizing | 0.1 | 1.43 | Ambiguous | 1.95 | Ambiguous | 0.73 | Ambiguous | -3.51 | Deleterious | 0.843 | Possibly Damaging | 0.403 | Benign | -1.44 | Pathogenic | 0.02 | Affected | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||
| c.1496G>T | R499I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the change as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely pathogenic. No tool predicts a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain or inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of evidence supports a pathogenic effect, and this is consistent with the absence of a ClinVar entry; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -9.069 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.713 | Likely Pathogenic | 0.1401 | 0.2146 | 1.53 | Ambiguous | 0.1 | 0.61 | Ambiguous | 1.07 | Ambiguous | 0.57 | Ambiguous | -5.50 | Deleterious | 0.998 | Probably Damaging | 0.922 | Probably Damaging | -1.47 | Pathogenic | 0.00 | Affected | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||
| c.1497A>C | R499S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499S is catalogued in gnomAD (ID 6‑33438529‑A‑C) but has no ClinVar entry. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool reports a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized and Foldetta are uncertain, whereas the SGM‑Consensus remains likely pathogenic. Protein‑stability predictions are inconclusive (FoldX uncertain, Rosetta pathogenic, Foldetta uncertain). Taken together, the overwhelming majority of evidence supports a pathogenic classification for R499S. This conclusion is consistent with the absence of a ClinVar status, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438529-A-C | 1 | 6.20e-7 | -9.559 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.632 | Likely Pathogenic | 0.2443 | 0.1649 | 1.03 | Ambiguous | 0.0 | 2.19 | Destabilizing | 1.61 | Ambiguous | 1.40 | Destabilizing | -2.69 | Deleterious | 0.958 | Probably Damaging | 0.702 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||
| c.1497A>T | R499S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499S is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta all predict pathogenicity, while FoldX, AlphaMissense‑Optimized, and Foldetta are uncertain. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic, and Foldetta likewise yields an uncertain result. Taken together, the overwhelming majority of reliable tools predict a pathogenic effect, and there is no ClinVar annotation to contradict this assessment. Therefore, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -9.559 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 0.632 | Likely Pathogenic | 0.2443 | 0.1649 | 1.03 | Ambiguous | 0.0 | 2.19 | Destabilizing | 1.61 | Ambiguous | 1.40 | Destabilizing | -2.69 | Deleterious | 0.958 | Probably Damaging | 0.702 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||
| c.1498C>A | L500M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The premPS score is uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. No other high‑accuracy predictions are available. Overall, the majority of high‑accuracy tools lean toward a benign interpretation, and this assessment does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -9.945 | Likely Pathogenic | 0.301 | Likely Benign | Likely Benign | 0.590 | Likely Pathogenic | 0.0710 | 0.2202 | 0.15 | Likely Benign | 0.0 | -0.09 | Likely Benign | 0.03 | Likely Benign | 0.92 | Ambiguous | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||
| c.1498C>G | L500V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L500V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign effect include SIFT and AlphaMissense‑Optimized, whereas a majority of tools predict pathogenicity: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -12.963 | Likely Pathogenic | 0.379 | Ambiguous | Likely Benign | 0.565 | Likely Pathogenic | 0.1205 | 0.1860 | 1.92 | Ambiguous | 0.0 | 0.81 | Ambiguous | 1.37 | Ambiguous | 1.11 | Destabilizing | -2.98 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.24 | Pathogenic | 0.11 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1499T>A | L500Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500Q has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are treated as unavailable. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized (benign) stands alone, whereas the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic. Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent pathogenic predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -13.431 | Likely Pathogenic | 0.649 | Likely Pathogenic | Likely Benign | 0.878 | Likely Pathogenic | 0.0950 | 0.0488 | 1.92 | Ambiguous | 0.1 | 1.78 | Ambiguous | 1.85 | Ambiguous | 1.49 | Destabilizing | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.35 | Pathogenic | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1499T>C | L500P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500P is listed in ClinVar (ID 2708686.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | Pathogenic | 1 | -15.898 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.894 | Likely Pathogenic | 0.3103 | 0.0625 | 5.91 | Destabilizing | 0.3 | 8.90 | Destabilizing | 7.41 | Destabilizing | 1.92 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||
| c.1499T>G | L500R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as pathogenic include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a benign effect; the benign group is empty. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overwhelming agreement among pathogenic predictors and the lack of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -15.576 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 0.794 | Likely Pathogenic | 0.1204 | 0.0488 | 2.23 | Destabilizing | 0.1 | 1.04 | Ambiguous | 1.64 | Ambiguous | 1.11 | Destabilizing | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.02 | Pathogenic | 0.03 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.149T>A | I50N 2D AIThe SynGAP1 missense variant I50N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as benign. Foldetta results are unavailable. Overall, the predictions are mixed, with an equal split between benign and pathogenic calls, but the most reliable single‑tool prediction (AlphaMissense‑Optimized) and the majority of individual tools lean toward pathogenicity. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -7.091 | In-Between | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.135 | Likely Benign | 0.0824 | 0.0412 | -2.37 | Neutral | 0.842 | Possibly Damaging | 0.272 | Benign | 3.73 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||
| c.149T>C | I50T 2D AIThe SynGAP1 missense variant I50T is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree that the change is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all classify it as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic effect. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments therefore point to a benign outcome: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is benign, and Foldetta data are missing. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -5.121 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.128 | Likely Benign | 0.0950 | 0.0708 | -1.61 | Neutral | 0.092 | Benign | 0.037 | Benign | 3.76 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||
| c.149T>G | I50S 2D AIThe SynGAP1 I50S missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM all classify it as benign. In contrast, SIFT and AlphaMissense‑Default predict a pathogenic impact. AlphaMissense‑Optimized yields an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this residue. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments therefore point to a benign outcome: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus is likely benign, and Foldetta data are missing. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -4.257 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.209 | Likely Benign | 0.2626 | 0.0800 | -2.03 | Neutral | 0.334 | Benign | 0.099 | Benign | 3.74 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||
| c.1501A>C | I501L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, Rosetta, Foldetta, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. Uncertain or inconclusive results are reported for FoldX, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign, all supporting a non‑deleterious effect. Based on the preponderance of benign predictions and the concordant high‑accuracy tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -7.348 | In-Between | 0.282 | Likely Benign | Likely Benign | 0.219 | Likely Benign | 0.0817 | 0.2261 | 0.78 | Ambiguous | 0.2 | -0.34 | Likely Benign | 0.22 | Likely Benign | 0.86 | Ambiguous | -1.92 | Neutral | 0.930 | Possibly Damaging | 0.985 | Probably Damaging | 3.51 | Benign | 0.05 | Affected | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||
| c.1501A>G | I501V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions from FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for I501V, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -2.326 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.200 | Likely Benign | 0.0985 | 0.2491 | 0.94 | Ambiguous | 0.0 | 0.56 | Ambiguous | 0.75 | Ambiguous | 0.06 | Likely Benign | 0.20 | Neutral | 0.951 | Possibly Damaging | 0.960 | Probably Damaging | 3.52 | Benign | 1.00 | Tolerated | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.1501A>T | I501F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I501F missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain (a stability method that integrates FoldX‑MD and Rosetta outputs). No predictions are missing or inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -12.113 | Likely Pathogenic | 0.664 | Likely Pathogenic | Likely Benign | 0.385 | Likely Benign | 0.0574 | 0.1594 | 3.06 | Destabilizing | 0.1 | 0.26 | Likely Benign | 1.66 | Ambiguous | 0.71 | Ambiguous | -3.88 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.1502T>A | I501N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, while a majority of tools (SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Uncertain results come from AlphaMissense‑Optimized, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, whereas the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta likewise remains inconclusive. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -11.105 | Likely Pathogenic | 0.854 | Likely Pathogenic | Ambiguous | 0.445 | Likely Benign | 0.0825 | 0.0270 | 2.22 | Destabilizing | 0.0 | 1.70 | Ambiguous | 1.96 | Ambiguous | 1.90 | Destabilizing | -6.13 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.1502T>C | I501T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and premPS, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | Uncertain | 1 | -5.996 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.362 | Likely Benign | 0.0972 | 0.0640 | 2.40 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.11 | Destabilizing | 1.57 | Destabilizing | -3.48 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.44 | Benign | 0.16 | Tolerated | 3.37 | 35 | 0 | -1 | -5.2 | -12.05 | 214.5 | 26.9 | 0.0 | 0.0 | 0.5 | 0.0 | X | Potentially Pathogenic | Ile501 is located near a hinge in the middle of an α-helix (res. Leu489-Glu519). The sec-butyl side chain of Ile501 is hydrophobically packed with other residues in the inter-helix space (e.g., Leu500, Tyr497, Phe679) in the WT simulations. In the variant simulations, the hydroxyl group of Thr501 forms a hydrogen bond with the backbone atoms of Tyr497 on the same α-helix, which may weaken the α-helix integrity. Additionally, the polar hydroxyl group of Thr501 is not suitable for the hydrophobic inter-helix space, and thus, the residue swap could affect protein folding. However, Ile501 is followed by Gly502, which facilitates a hinge in the middle of the α-helix, making further weakening caused by Thr501 unlikely to be harmful to the α-helix integrity. | ||||||||||||
| c.1502T>G | I501S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized; all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized indicates a benign change, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. Overall, the preponderance of evidence points to a pathogenic effect for I501S. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -9.914 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.511 | Likely Pathogenic | 0.2370 | 0.0858 | 3.23 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.82 | Destabilizing | 1.79 | Destabilizing | -5.14 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.04 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.1503T>G | I501M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions that are inconclusive or unavailable are FoldX, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign impact for I501M. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -7.452 | In-Between | 0.259 | Likely Benign | Likely Benign | 0.294 | Likely Benign | 0.0680 | 0.1589 | 1.32 | Ambiguous | 0.2 | -0.19 | Likely Benign | 0.57 | Ambiguous | 0.95 | Ambiguous | -2.32 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||
| c.1504G>A | G502S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502S is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts a benign outcome, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -11.357 | Likely Pathogenic | 0.616 | Likely Pathogenic | Likely Benign | 0.839 | Likely Pathogenic | 0.2429 | 0.3217 | 2.09 | Destabilizing | 0.6 | 0.71 | Ambiguous | 1.40 | Ambiguous | 0.96 | Ambiguous | -5.74 | Deleterious | 0.975 | Probably Damaging | 0.862 | Possibly Damaging | -1.64 | Pathogenic | 0.01 | Affected | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||
| c.1504G>C | G502R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS, which is listed as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -15.571 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.917 | Likely Pathogenic | 0.1014 | 0.3317 | 8.80 | Destabilizing | 0.3 | 10.07 | Destabilizing | 9.44 | Destabilizing | 0.88 | Ambiguous | -7.73 | Deleterious | 1.000 | Probably Damaging | 0.985 | Probably Damaging | -1.65 | Pathogenic | 0.00 | Affected | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.1504G>T | G502C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502C lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include only premPS. The majority of tools predict a pathogenic effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Tools with uncertain or inconclusive outputs are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the preponderance of evidence points to a pathogenic impact for G502C, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -12.086 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.845 | Likely Pathogenic | 0.1279 | 0.2691 | 1.02 | Ambiguous | 0.5 | 1.55 | Ambiguous | 1.29 | Ambiguous | 0.30 | Likely Benign | -8.65 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | -1.67 | Pathogenic | 0.00 | Affected | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||
| c.1505G>A | G502D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | Uncertain | 1 | -14.796 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.915 | Likely Pathogenic | 0.1715 | 0.1172 | 3.79 | Destabilizing | 0.9 | 5.69 | Destabilizing | 4.74 | Destabilizing | 1.38 | Destabilizing | -6.80 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | -1.66 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 1 | -1 | -3.1 | 58.04 | 224.2 | -80.0 | -0.8 | 0.7 | 0.6 | 0.3 | X | X | X | Potentially Pathogenic | Gly502 is located in a hinge in the middle of an α-helix (res. Leu489-Glu519). In the WT, Gly502 acts as an α-helix breaker due to its lack of a side chain, facilitating a bend in the middle of the α-helix. In the variant simulations, the carboxylate group of Asp502 forms hydrogen bonds with neighboring residues (e.g., Ser677, Lys504), disrupting the hinge. Additionally, Asp502 struggles to fit into the α-helix hinge and cannot generate a similar bend as Gly502, which would drastically affect the secondary structure during folding. Thus, the deleterious effect seen in the simulations is likely an underestimate of the impact of the residue swap on the protein structure during protein folding. | ||||||||||
| c.1505G>C | G502A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G502A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Foldetta, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized indicates a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—concludes pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact for G502A, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -10.191 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 0.725 | Likely Pathogenic | 0.3548 | 0.3393 | 0.82 | Ambiguous | 0.4 | -0.53 | Ambiguous | 0.15 | Likely Benign | 0.54 | Ambiguous | -5.64 | Deleterious | 0.512 | Possibly Damaging | 0.157 | Benign | -1.59 | Pathogenic | 0.17 | Tolerated | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1505G>T | G502V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: all evaluated algorithms except premPS (which predicts benign) classify the substitution as pathogenic or likely pathogenic. The consensus of high‑accuracy predictors is consistent: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a destabilizing, pathogenic outcome. In contrast, premPS is the sole tool suggesting a benign impact. Overall, the overwhelming majority of evidence points to a pathogenic effect for G502V, and this conclusion does not conflict with the absence of a ClinVar classification. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -15.278 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.917 | Likely Pathogenic | 0.1406 | 0.3387 | 3.56 | Destabilizing | 1.0 | 5.50 | Destabilizing | 4.53 | Destabilizing | 0.43 | Likely Benign | -8.65 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | -1.67 | Pathogenic | 0.00 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| c.1507C>A | Q503K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503K is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools lean toward a benign effect, and this conclusion is not contradicted by ClinVar data, which contains no entry for this variant. Thus, the variant is most likely benign, with no ClinVar evidence contradicting this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -12.276 | Likely Pathogenic | 0.217 | Likely Benign | Likely Benign | 0.603 | Likely Pathogenic | 0.1601 | 0.2419 | -0.01 | Likely Benign | 0.1 | -0.26 | Likely Benign | -0.14 | Likely Benign | 0.70 | Ambiguous | -3.37 | Deleterious | 0.676 | Possibly Damaging | 0.297 | Benign | -1.42 | Pathogenic | 0.12 | Tolerated | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||
| c.1507C>G | Q503E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and Rosetta. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Overall, the majority of available predictions favor a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -7.909 | In-Between | 0.146 | Likely Benign | Likely Benign | 0.410 | Likely Benign | 0.1168 | 0.1508 | 0.51 | Ambiguous | 0.1 | 2.11 | Destabilizing | 1.31 | Ambiguous | 0.85 | Ambiguous | -2.21 | Neutral | 0.931 | Possibly Damaging | 0.500 | Possibly Damaging | -1.43 | Pathogenic | 0.17 | Tolerated | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||
| c.1508A>C | Q503P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; the remaining tools (FoldX, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts benign, but the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta both predict pathogenic. Because the majority of evidence points to a deleterious effect, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -10.915 | Likely Pathogenic | 0.414 | Ambiguous | Likely Benign | 0.860 | Likely Pathogenic | 0.2076 | 0.3610 | 1.06 | Ambiguous | 0.7 | 5.94 | Destabilizing | 3.50 | Destabilizing | 0.75 | Ambiguous | -5.20 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | -1.53 | Pathogenic | 0.03 | Affected | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.1508A>G | Q503R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. The high‑accuracy methods give a benign result for AlphaMissense‑Optimized, a pathogenic result for the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign result for Foldetta (combining FoldX‑MD and Rosetta). Overall, the majority of tools and the high‑accuracy methods lean toward a benign effect. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -11.396 | Likely Pathogenic | 0.232 | Likely Benign | Likely Benign | 0.640 | Likely Pathogenic | 0.1426 | 0.0963 | -0.40 | Likely Benign | 0.3 | 0.60 | Ambiguous | 0.10 | Likely Benign | 0.50 | Likely Benign | -3.34 | Deleterious | 0.577 | Possibly Damaging | 0.395 | Benign | -1.42 | Pathogenic | 0.06 | Tolerated | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||
| c.1508A>T | Q503L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503L is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, premPS, Rosetta, and polyPhen‑2 (HumVar). Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, and FATHMM; FoldX is uncertain and therefore not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the majority of tools (seven versus six) predict pathogenicity, and the high‑accuracy trio is split but leans toward pathogenic. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -8.203 | Likely Pathogenic | 0.261 | Likely Benign | Likely Benign | 0.711 | Likely Pathogenic | 0.0715 | 0.3578 | -0.56 | Ambiguous | 0.2 | -0.07 | Likely Benign | -0.32 | Likely Benign | 0.24 | Likely Benign | -6.29 | Deleterious | 0.911 | Possibly Damaging | 0.369 | Benign | -1.52 | Pathogenic | 0.05 | Affected | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||
| c.1509G>C | Q503H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are therefore considered unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta remains uncertain. Overall, the majority of evaluated predictors (7 benign vs. 3 pathogenic) lean toward a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -5.335 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.331 | Likely Benign | 0.1091 | 0.2125 | 0.94 | Ambiguous | 0.2 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.48 | Likely Benign | -3.40 | Deleterious | 0.002 | Benign | 0.004 | Benign | -1.52 | Pathogenic | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||
| c.1509G>T | Q503H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are therefore considered unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta remains uncertain. Overall, the majority of evaluated predictors (7 benign vs. 3 pathogenic) lean toward a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -5.335 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.331 | Likely Benign | 0.1091 | 0.2125 | 0.94 | Ambiguous | 0.2 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.48 | Likely Benign | -3.40 | Deleterious | 0.002 | Benign | 0.004 | Benign | -1.52 | Pathogenic | 0.01 | Affected | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||
| c.150C>G | I50M 2D AIThe SynGAP1 missense variant I50M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools indicates that the I50M variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.295083 | Structured | 0.449965 | Uncertain | 0.545 | 0.708 | 0.000 | -5.707 | Likely Benign | 0.383 | Ambiguous | Likely Benign | 0.030 | Likely Benign | 0.0603 | 0.2524 | -0.95 | Neutral | 0.637 | Possibly Damaging | 0.202 | Benign | 3.76 | Benign | 0.00 | Affected | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.1510A>C | K504Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K504Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign stability change. Overall, seven tools support a benign outcome while four support pathogenicity, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -6.685 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.269 | Likely Benign | 0.3104 | 0.0780 | 0.13 | Likely Benign | 0.2 | -0.01 | Likely Benign | 0.06 | Likely Benign | 0.91 | Ambiguous | -3.07 | Deleterious | 0.945 | Possibly Damaging | 0.918 | Probably Damaging | -1.37 | Pathogenic | 0.46 | Tolerated | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||
| c.1510A>G | K504E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -9.890 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | 0.386 | Likely Benign | 0.2583 | 0.0650 | 0.63 | Ambiguous | 0.4 | 0.78 | Ambiguous | 0.71 | Ambiguous | 1.06 | Destabilizing | -3.40 | Deleterious | 0.924 | Possibly Damaging | 0.674 | Possibly Damaging | -1.25 | Pathogenic | 0.21 | Tolerated | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1511A>C | K504T 2D 3DClick to see structure in 3D Viewer AISynGAP1 K504T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Other tools (AlphaMissense‑Default, Foldetta, premPS, Rosetta) were inconclusive and are not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions support a pathogenic classification, and this is not contradicted by the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -9.572 | Likely Pathogenic | 0.494 | Ambiguous | Likely Benign | 0.498 | Likely Benign | 0.1482 | 0.2619 | 0.12 | Likely Benign | 0.3 | -0.85 | Ambiguous | -0.37 | Likely Benign | 0.84 | Ambiguous | -5.36 | Deleterious | 0.961 | Probably Damaging | 0.990 | Probably Damaging | -1.44 | Pathogenic | 0.10 | Tolerated | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1511A>G | K504R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438543‑A‑G). Consensus from most in‑silico predictors is benign: REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a benign effect, while only FATHMM predicts pathogenicity. Uncertain calls come from Rosetta and premPS. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | Uncertain | 1 | 6-33438543-A-G | 2 | 1.24e-6 | -4.365 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.238 | Likely Benign | 0.3363 | 0.0647 | 0.13 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.32 | Likely Benign | 0.94 | Ambiguous | -2.16 | Neutral | 0.002 | Benign | 0.015 | Benign | -1.41 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||
| c.1511A>T | K504I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504I is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect fall into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized; pathogenic predictions include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus as pathogenic. Because the majority of tools (seven) predict pathogenicity while three high‑accuracy methods provide conflicting evidence, the overall prediction leans toward pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -12.597 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.491 | Likely Benign | 0.0769 | 0.2713 | -0.04 | Likely Benign | 0.3 | -0.36 | Likely Benign | -0.20 | Likely Benign | 0.40 | Likely Benign | -7.35 | Deleterious | 0.996 | Probably Damaging | 0.993 | Probably Damaging | -1.49 | Pathogenic | 0.02 | Affected | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||
| c.1512A>C | K504N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K504N is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (8/13) predict pathogenicity, while 4 predict benign and one is uncertain. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -8.908 | Likely Pathogenic | 0.720 | Likely Pathogenic | Likely Benign | 0.430 | Likely Benign | 0.2470 | 0.0926 | 0.26 | Likely Benign | 0.2 | 0.57 | Ambiguous | 0.42 | Likely Benign | 1.00 | Destabilizing | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.922 | Probably Damaging | -1.44 | Pathogenic | 0.07 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1512A>T | K504N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K504N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, AlphaMissense‑Optimized, and the folding‑stability method Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta indicating a benign folding‑stability outcome. Overall, the majority of predictions (8 out of 13) support a pathogenic interpretation. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.304984 | Uncertain | 0.850 | 0.189 | 0.000 | -8.908 | Likely Pathogenic | 0.720 | Likely Pathogenic | Likely Benign | 0.430 | Likely Benign | 0.2470 | 0.0926 | 0.26 | Likely Benign | 0.2 | 0.57 | Ambiguous | 0.42 | Likely Benign | 1.00 | Destabilizing | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.922 | Probably Damaging | -1.44 | Pathogenic | 0.07 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1513T>A | Y505N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools largely agree on a deleterious effect: all available predictors except FATHMM classify the variant as pathogenic or likely pathogenic. The benign group contains only FATHMM, whereas the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -14.139 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.695 | Likely Pathogenic | 0.2124 | 0.0612 | 3.38 | Destabilizing | 0.0 | 4.33 | Destabilizing | 3.86 | Destabilizing | 2.47 | Destabilizing | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.1513T>C | Y505H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505H is listed in ClinVar as Pathogenic (ClinVar ID 3064218.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also Pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among predictive tools, the variant is most likely pathogenic, consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | Likely Pathogenic | 1 | -11.383 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.646 | Likely Pathogenic | 0.2148 | 0.0612 | 2.91 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.90 | Destabilizing | 1.60 | Destabilizing | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.64 | Benign | 0.00 | Affected | 3.37 | 35 | 2 | 0 | -1.9 | -26.03 | |||||||||||||||||||||
| c.1513T>G | Y505D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505D is listed in ClinVar as Pathogenic (ClinVar ID 3172759.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect are limited to FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | Likely Pathogenic | 1 | -14.078 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.718 | Likely Pathogenic | 0.3940 | 0.0612 | 4.98 | Destabilizing | 0.1 | 4.72 | Destabilizing | 4.85 | Destabilizing | 2.49 | Destabilizing | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 3.37 | 35 | -3 | -4 | -2.2 | -48.09 | |||||||||||||||||||||
| c.1514A>C | Y505S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only FATHMM, whereas all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No predictions are missing or inconclusive. Overall, the consensus of the available computational evidence indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently contains no entry for Y505S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -14.053 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.559 | Likely Pathogenic | 0.4056 | 0.1945 | 3.49 | Destabilizing | 0.1 | 4.86 | Destabilizing | 4.18 | Destabilizing | 2.33 | Destabilizing | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.61 | Benign | 0.00 | Affected | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.1514A>G | Y505C 2D AIThe SynGAP1 missense variant Y505C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support this: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -11.784 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.578 | Likely Pathogenic | 0.3203 | 0.1814 | 3.41 | Destabilizing | 0.5 | 4.37 | Destabilizing | 3.89 | Destabilizing | 2.32 | Destabilizing | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.1514A>T | Y505F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y505F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (five benign versus four pathogenic) lean toward a benign interpretation, and this is consistent with the lack of ClinVar evidence; thus the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.047319 | Structured | 0.292227 | Uncertain | 0.909 | 0.188 | 0.000 | -8.855 | Likely Pathogenic | 0.437 | Ambiguous | Likely Benign | 0.434 | Likely Benign | 0.2409 | 0.2598 | 0.40 | Likely Benign | 0.0 | 0.76 | Ambiguous | 0.58 | Ambiguous | 0.69 | Ambiguous | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.93 | Benign | 0.07 | Tolerated | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||
| c.1516C>A | L506I 2D AIThe SynGAP1 missense variant L506I is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments give a pathogenic verdict from Foldetta (a combined FoldX‑MD/Rosetta stability analysis) and from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). AlphaMissense‑Optimized, however, predicts benign. Overall, the majority of reliable tools and the high‑accuracy methods favor a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -10.386 | Likely Pathogenic | 0.501 | Ambiguous | Likely Benign | 0.365 | Likely Benign | 0.0745 | 0.2033 | 1.73 | Ambiguous | 1.0 | 2.85 | Destabilizing | 2.29 | Destabilizing | 0.98 | Ambiguous | -1.99 | Neutral | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.01 | Affected | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1516C>G | L506V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM Consensus) all indicate a pathogenic impact. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -10.220 | Likely Pathogenic | 0.512 | Ambiguous | Likely Benign | 0.420 | Likely Benign | 0.1126 | 0.1660 | 2.61 | Destabilizing | 0.2 | 3.27 | Destabilizing | 2.94 | Destabilizing | 1.36 | Destabilizing | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.62 | Pathogenic | 0.04 | Affected | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.1516C>T | L506F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; premPS and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which is consistent with its ClinVar “Uncertain” classification and does not contradict the available data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | Uncertain | 1 | -11.262 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 0.464 | Likely Benign | 0.0566 | 0.1471 | 4.92 | Destabilizing | 0.8 | 5.76 | Destabilizing | 5.34 | Destabilizing | 0.91 | Ambiguous | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.62 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0 | 2 | -1.0 | 34.02 | |||||||||||||||||||||
| c.1517T>A | L506H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -12.999 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.758 | Likely Pathogenic | 0.0919 | 0.0488 | 4.45 | Destabilizing | 0.3 | 3.47 | Destabilizing | 3.96 | Destabilizing | 2.18 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||
| c.1517T>C | L506P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506P is listed in ClinVar (ID 975474.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | Likely Pathogenic | 1 | -12.088 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.737 | Likely Pathogenic | 0.3047 | 0.0625 | 5.48 | Destabilizing | 0.7 | 10.19 | Destabilizing | 7.84 | Destabilizing | 2.50 | Destabilizing | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -3 | -3 | -5.4 | -16.04 | 182.6 | 64.9 | 0.1 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | Leu506 is located in the middle of an α-helix (res. Gly502-Tyr518) within the inter-helix space of two helices (res. Gly502-Tyr518 and res. Glu582-Met603). In the WT simulations, the iso-butyl side chain of Leu506 hydrophobically packs with residues in the inter-helix space (e.g., Ile510, Phe597, Leu598, Ala601). In the variant simulations, the cyclic five-membered pyrrolidine ring of Pro506 is not as optimal as Leu506 for hydrophobic packing with nearby residues. Additionally, Pro506 cannot maintain the hydrogen bond with the backbone oxygen of Gly502 as Leu506 does in the WT, which disrupts the secondary structure element. | ||||||||||||
| c.1517T>G | L506R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L506R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, all available evidence indicates that the variant is most likely pathogenic, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -14.119 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.738 | Likely Pathogenic | 0.1207 | 0.0488 | 4.92 | Destabilizing | 0.6 | 5.85 | Destabilizing | 5.39 | Destabilizing | 1.77 | Destabilizing | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1519A>C | K507Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta, premPS, and ESM1b. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Taken together, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -7.698 | In-Between | 0.180 | Likely Benign | Likely Benign | 0.443 | Likely Benign | 0.2952 | 0.0713 | 0.28 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.21 | Likely Benign | -0.52 | Ambiguous | 0.22 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.52 | Pathogenic | 0.86 | Tolerated | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||
| c.1519A>G | K507E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K507E missense change is not listed in ClinVar and has no gnomAD allele, indicating it is not a common polymorphism. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Four tools give uncertain results: FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments provide a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic, and Foldetta remains uncertain. Overall, the majority of standard predictors favor a pathogenic effect, and the high‑accuracy consensus also tilts toward pathogenicity, though not decisively. Therefore, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -11.507 | Likely Pathogenic | 0.448 | Ambiguous | Likely Benign | 0.536 | Likely Pathogenic | 0.2537 | 0.0488 | 0.70 | Ambiguous | 0.0 | 0.31 | Likely Benign | 0.51 | Ambiguous | 0.67 | Ambiguous | -0.84 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.21 | Tolerated | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||
| c.151A>C | I51L 2D AIThe SynGAP1 missense variant I51L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | 0.408 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.080 | Likely Benign | 0.0924 | 0.3993 | 0.14 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.35 | Benign | 0.00 | Affected | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||
| c.151A>G | I51V 2D AIThe SynGAP1 missense variant I51V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -3.397 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.1330 | 0.3602 | -0.24 | Neutral | 0.004 | Benign | 0.007 | Benign | 4.26 | Benign | 0.00 | Affected | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||||||||
| c.151A>T | I51F 2D AIThe SynGAP1 missense variant I51F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for I51F, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -5.687 | Likely Benign | 0.526 | Ambiguous | Likely Benign | 0.114 | Likely Benign | 0.0565 | 0.3070 | -0.87 | Neutral | 0.099 | Benign | 0.039 | Benign | 4.13 | Benign | 0.00 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||
| c.1520A>C | K507T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K507T missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT, Rosetta, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the absence of a ClinVar classification. **The variant is most likely pathogenic based on the current predictive evidence.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.244 | Likely Pathogenic | 0.468 | Ambiguous | Likely Benign | 0.724 | Likely Pathogenic | 0.1501 | 0.2451 | 0.82 | Ambiguous | 0.1 | 0.31 | Likely Benign | 0.57 | Ambiguous | 0.78 | Ambiguous | -2.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.55 | Pathogenic | 0.12 | Tolerated | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||
| c.1520A>G | K507R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K507R is not listed in ClinVar (ClinVar status: not reported) but is present in gnomAD (gnomAD ID 6-33438552-A-G). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no pathogenic annotation for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | 6-33438552-A-G | 1 | 6.20e-7 | -7.363 | In-Between | 0.085 | Likely Benign | Likely Benign | 0.503 | Likely Pathogenic | 0.3155 | 0.0579 | -0.08 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.15 | Likely Benign | 0.36 | Likely Benign | -0.68 | Neutral | 0.992 | Probably Damaging | 0.980 | Probably Damaging | -1.48 | Pathogenic | 0.27 | Tolerated | 3.37 | 35 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||
| c.1520A>T | K507M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K507M missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, more tools (8) predict pathogenicity than benign (5), and the high‑accuracy consensus leans toward pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -9.548 | Likely Pathogenic | 0.576 | Likely Pathogenic | Likely Benign | 0.850 | Likely Pathogenic | 0.0783 | 0.2251 | 0.12 | Likely Benign | 0.1 | -0.74 | Ambiguous | -0.31 | Likely Benign | -0.22 | Likely Benign | -2.39 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.63 | Pathogenic | 0.03 | Affected | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||
| c.1521G>C | K507N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas a pathogenic signal is reported by REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta’s stability prediction is unavailable. Overall, the majority of tools (10 out of 14 with definitive calls) predict a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.682 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.579 | Likely Pathogenic | 0.2417 | 0.0764 | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1521G>T | K507N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K507N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict a pathogenic effect comprise REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (10 pathogenic vs. 4 benign) predict a deleterious impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.262601 | Uncertain | 0.885 | 0.222 | 0.000 | -10.682 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.579 | Likely Pathogenic | 0.2417 | 0.0764 | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||
| c.1522G>A | D508N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS, FATHMM, AlphaMissense‑Optimized) and pathogenic predictions (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b). Three tools remain uncertain (Rosetta, Foldetta, AlphaMissense‑Default). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized classifies the change as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns a pathogenic verdict; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an inconclusive result. Because the consensus of the high‑accuracy methods is split, the overall prediction is ambiguous, but the balance of evidence leans toward pathogenicity. This assessment does not contradict ClinVar, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -9.909 | Likely Pathogenic | 0.411 | Ambiguous | Likely Benign | 0.265 | Likely Benign | 0.1577 | 0.4599 | 0.11 | Likely Benign | 0.1 | 1.24 | Ambiguous | 0.68 | Ambiguous | -0.12 | Likely Benign | -4.62 | Deleterious | 0.870 | Possibly Damaging | 0.615 | Possibly Damaging | 3.32 | Benign | 0.04 | Affected | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.1522G>C | D508H 2D AISynGAP1 D508H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show an even split: benign calls come from REVEL, FoldX, premPS, SIFT, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain outcome from AlphaMissense‑Optimized, and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.074 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.336 | Likely Benign | 0.1804 | 0.5096 | 0.15 | Likely Benign | 0.4 | 0.97 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.919 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.1522G>T | D508Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508Y missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign outcome. Overall, the majority of evidence (seven pathogenic vs. five benign) points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.917 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | 0.363 | Likely Benign | 0.0908 | 0.4736 | -0.53 | Ambiguous | 0.2 | 0.72 | Ambiguous | 0.10 | Likely Benign | 0.06 | Likely Benign | -8.37 | Deleterious | 1.000 | Probably Damaging | 0.965 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||
| c.1523A>C | D508A 2D 3DClick to see structure in 3D Viewer AISynGAP1 D508A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give a split result: AlphaMissense‑Optimized predicts benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is uncertain. No prediction or stability result is missing; all available outputs are considered. Overall, the predictions are evenly divided between benign and pathogenic, with no clear consensus. Therefore, the variant is inconclusive; it is not contradictory to the ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -11.434 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.339 | Likely Benign | 0.3758 | 0.4241 | -0.18 | Likely Benign | 0.2 | 1.84 | Ambiguous | 0.83 | Ambiguous | 0.09 | Likely Benign | -7.37 | Deleterious | 0.988 | Probably Damaging | 0.762 | Possibly Damaging | 3.37 | Benign | 0.06 | Tolerated | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.1523A>G | D508G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508G missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta. FoldX‑MD is inconclusive and is treated as unavailable. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus, and a pathogenic prediction from Foldetta. Overall, the majority of evidence, including the high‑accuracy tools, supports a pathogenic effect. This conclusion does not contradict ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -8.478 | Likely Pathogenic | 0.622 | Likely Pathogenic | Likely Benign | 0.368 | Likely Benign | 0.3821 | 0.4528 | 0.87 | Ambiguous | 0.2 | 3.20 | Destabilizing | 2.04 | Destabilizing | 0.13 | Likely Benign | -6.61 | Deleterious | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 3.30 | Benign | 0.07 | Tolerated | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||
| c.1523A>T | D508V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508V missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (a folding‑stability method combining FoldX‑MD and Rosetta outputs) as benign. With seven benign versus six pathogenic calls and two of the three high‑accuracy tools supporting benign, the variant is most likely benign. This conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -13.529 | Likely Pathogenic | 0.691 | Likely Pathogenic | Likely Benign | 0.381 | Likely Benign | 0.1050 | 0.4604 | 0.07 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.37 | Likely Benign | 0.07 | Likely Benign | -8.37 | Deleterious | 0.985 | Probably Damaging | 0.895 | Possibly Damaging | 3.27 | Benign | 0.08 | Tolerated | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||
| c.1524T>A | D508E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D508E is reported in gnomAD (ID 6‑33438556‑T‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the protein‑stability method Foldetta. Only PROVEAN predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | 6-33438556-T-A | 1 | 6.20e-7 | -5.959 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.1766 | 0.4304 | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||
| c.1524T>G | D508E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all classify the change as benign. Only PROVEAN predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -5.959 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.1766 | 0.4304 | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||
| c.1525G>A | A509T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain and therefore unavailable for interpretation. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -8.961 | Likely Pathogenic | 0.171 | Likely Benign | Likely Benign | 0.360 | Likely Benign | 0.1344 | 0.5593 | 0.95 | Ambiguous | 0.4 | 0.61 | Ambiguous | 0.78 | Ambiguous | 0.04 | Likely Benign | -2.15 | Neutral | 0.031 | Benign | 0.058 | Benign | -1.25 | Pathogenic | 0.32 | Tolerated | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||
| c.1525G>C | A509P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status (no report). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -13.234 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.884 | Likely Pathogenic | 0.1940 | 0.4570 | 5.82 | Destabilizing | 0.6 | 7.70 | Destabilizing | 6.76 | Destabilizing | 1.13 | Destabilizing | -4.15 | Deleterious | 0.987 | Probably Damaging | 0.844 | Possibly Damaging | -1.39 | Pathogenic | 0.01 | Affected | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1525G>T | A509S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Four tools give uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS). High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta is also inconclusive. Overall, the majority of standard predictors lean toward pathogenicity, while the most reliable single‑tool prediction (AlphaMissense‑Optimized) suggests benign. Given the balance of evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -9.997 | Likely Pathogenic | 0.171 | Likely Benign | Likely Benign | 0.621 | Likely Pathogenic | 0.2410 | 0.4384 | 0.83 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.23 | Ambiguous | 0.59 | Ambiguous | -2.18 | Neutral | 0.119 | Benign | 0.468 | Possibly Damaging | -1.35 | Pathogenic | 0.01 | Affected | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||
| c.1526C>A | A509D 2D AIThe SynGAP1 missense variant A509D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Pathogenic” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -17.026 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.915 | Likely Pathogenic | 0.1610 | 0.1360 | 4.02 | Destabilizing | 1.6 | 3.09 | Destabilizing | 3.56 | Destabilizing | 1.36 | Destabilizing | -4.94 | Deleterious | 0.963 | Probably Damaging | 0.844 | Possibly Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.1526C>G | A509G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that clearly indicate benign effect include only AlphaMissense‑Optimized. All other evaluated tools that provide a definitive call predict pathogenicity: SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Tools with inconclusive results (AlphaMissense‑Default, FoldX, and Foldetta) are treated as unavailable and do not influence the overall assessment. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, combining FoldX‑MD (uncertain) and Rosetta (pathogenic), is uncertain. Overall, the majority of definitive predictions support a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -11.873 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 0.804 | Likely Pathogenic | 0.2193 | 0.4213 | 1.36 | Ambiguous | 0.2 | 2.33 | Destabilizing | 1.85 | Ambiguous | 1.14 | Destabilizing | -3.57 | Deleterious | 0.911 | Possibly Damaging | 0.706 | Possibly Damaging | -1.39 | Pathogenic | 0.00 | Affected | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1526C>T | A509V 2D 3DClick to see structure in 3D Viewer AISynGAP1 A509V is not reported in ClinVar and is absent from gnomAD. High‑accuracy predictors give mixed results: AlphaMissense‑Optimized classifies the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive because FoldX is uncertain and Rosetta is benign. Among the remaining tools, benign predictions come from REVEL, Rosetta, premPS, polyPhen2_HumDiv, polyPhen2_HumVar, and SIFT, whereas pathogenic predictions come from SGM‑Consensus, PROVEAN, ESM1b, and FATHMM. AlphaMissense‑Default and FoldX remain uncertain. Overall, the majority of evidence points toward a benign effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -11.987 | Likely Pathogenic | 0.382 | Ambiguous | Likely Benign | 0.474 | Likely Benign | 0.1333 | 0.5706 | 0.52 | Ambiguous | 0.5 | 0.35 | Likely Benign | 0.44 | Likely Benign | -0.25 | Likely Benign | -3.11 | Deleterious | 0.064 | Benign | 0.048 | Benign | -1.15 | Pathogenic | 0.18 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1528A>C | I510L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all indicate a benign effect. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -2.362 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.338 | Likely Benign | 0.0819 | 0.2461 | 0.31 | Likely Benign | 0.2 | -0.05 | Likely Benign | 0.13 | Likely Benign | -1.01 | Stabilizing | 0.69 | Neutral | 0.016 | Benign | 0.130 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||
| c.1528A>G | I510V 2D 3DClick to see structure in 3D Viewer AISynGAP1 I510V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, FATHMM, and premPS. FoldX and Rosetta analyses are inconclusive, and Foldetta stability assessment is unavailable. High‑accuracy methods reinforce the benign trend: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta provides no definitive result. Overall, the majority of evidence points to a benign effect for I510V, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -6.072 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.461 | Likely Benign | 0.0999 | 0.2291 | 1.45 | Ambiguous | 0.2 | 0.50 | Ambiguous | 0.98 | Ambiguous | 1.13 | Destabilizing | -1.00 | Neutral | 0.792 | Possibly Damaging | 0.332 | Benign | -1.36 | Pathogenic | 0.02 | Affected | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.1528A>T | I510F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and AlphaMissense‑Optimized, whereas the majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta) predict a pathogenic impact; Rosetta remains uncertain. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -8.185 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.692 | Likely Pathogenic | 0.0552 | 0.1794 | 4.66 | Destabilizing | 0.7 | 1.38 | Ambiguous | 3.02 | Destabilizing | 0.50 | Likely Benign | -2.64 | Deleterious | 0.991 | Probably Damaging | 0.854 | Possibly Damaging | -1.14 | Pathogenic | 0.01 | Affected | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||
| c.1529T>A | I510N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic impact. Based on the uniform predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -12.784 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.925 | Likely Pathogenic | 0.0761 | 0.0270 | 3.09 | Destabilizing | 0.1 | 3.00 | Destabilizing | 3.05 | Destabilizing | 2.08 | Destabilizing | -5.62 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.1529T>C | I510T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta—classify the variant as pathogenic, while Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -9.993 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.914 | Likely Pathogenic | 0.0960 | 0.0440 | 3.08 | Destabilizing | 0.2 | 1.99 | Ambiguous | 2.54 | Destabilizing | 1.95 | Destabilizing | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.43 | Pathogenic | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.1529T>G | I510S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510S is listed in ClinVar as Pathogenic (ClinVar ID 449946.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect all converge on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool predicts a benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | Likely Pathogenic | 1 | -11.661 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.926 | Likely Pathogenic | 0.2395 | 0.0858 | 4.00 | Destabilizing | 0.1 | 3.78 | Destabilizing | 3.89 | Destabilizing | 2.34 | Destabilizing | -4.63 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -1 | -2 | -5.3 | -26.08 | 201.4 | 45.9 | -0.4 | 0.2 | 0.0 | 0.3 | X | Potentially Pathogenic | Ile510 is located in the middle of an α-helix (res. Gly502-Tyr518) within the inter-helix space of three helices (res. Gly502-Tyr518, Ala533-Val560, and res. Glu582-Met603). In the WT simulations, the sec-butyl side chain of Ile510 hydrophobically packs with other residues in the inter-helix space (e.g., Leu506, Leu610, Ile514, Ile602, Leu598). In the variant simulations, the hydroxyl group of Ser510 forms a hydrogen bond with the backbone atoms of Leu506 and Gly511 in the same α-helix, which could further weaken the α-helix integrity. This α-helix already shows weakness in the WT simulations due to Gly511. Although the simulations do not show large-scale effects, the residue swap could have a substantial impact due to the fundamental role of hydrophobic packing during protein folding. | ||||||||||||
| c.152T>A | I51N 2D AIThe SynGAP1 missense variant I51N is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD: not present). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available output for this variant. Consequently, the evidence is split evenly between benign and pathogenic predictions, with no decisive support from the most accurate methods. The variant is therefore inconclusive; it is not contradicted by any ClinVar record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -9.287 | Likely Pathogenic | 0.909 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.1005 | 0.0769 | -1.77 | Neutral | 0.704 | Possibly Damaging | 0.272 | Benign | 4.13 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||
| c.152T>C | I51T 2D AIThe SynGAP1 missense variant I51T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign, AlphaMissense‑Optimized remains Uncertain, and no Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -5.861 | Likely Benign | 0.881 | Likely Pathogenic | Ambiguous | 0.135 | Likely Benign | 0.1180 | 0.1265 | -1.07 | Neutral | 0.084 | Benign | 0.050 | Benign | 4.16 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||
| c.152T>G | I51S 2D AIThe SynGAP1 missense variant I51S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The remaining tools, ESM1b and AlphaMissense‑Optimized, are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (2 benign vs. 1 pathogenic vote). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -7.603 | In-Between | 0.879 | Likely Pathogenic | Ambiguous | 0.220 | Likely Benign | 0.3142 | 0.0957 | -1.39 | Neutral | 0.182 | Benign | 0.099 | Benign | 4.15 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||
| c.1530T>G | I510M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I510M missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign impact include PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (benign), ESM1b (uncertain), FATHMM (pathogenic), and PROVEAN (benign)—also favors benign. Foldetta, a protein‑folding stability method, yielded an uncertain outcome. Taken together, the consensus of the most reliable predictors indicates a benign effect. This conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -7.988 | In-Between | 0.235 | Likely Benign | Likely Benign | 0.532 | Likely Pathogenic | 0.0674 | 0.1789 | 0.56 | Ambiguous | 0.3 | 1.61 | Ambiguous | 1.09 | Ambiguous | 0.55 | Ambiguous | -0.97 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.42 | Pathogenic | 0.02 | Affected | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||
| c.1531G>A | G511R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G511R is listed in ClinVar as Pathogenic (ClinVar ID 1774641.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Stability calculations from FoldX and Rosetta are uncertain, and premPS is unavailable. Overall, the majority of evidence points to a pathogenic impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | Likely Pathogenic | 1 | -11.327 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.416 | Likely Benign | 0.1307 | 0.4104 | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | -3 | -2 | -4.1 | 99.14 | 279.4 | -159.9 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | Potentially Pathogenic | Gly511 is located in an α-helix (res. Gly502-Tyr518), facing hydrophobic residues in an inter-helix space (e.g., Leu610, Ile514) in the WT simulations. In contrast, in the variant simulations, the bulkier and positively charged guanidinium side chain of Arg511 forms a salt bridge with the carboxylate group of Glu217 or hydrogen bonds with the backbone carbonyl group of Leu610. Although the residue swap introduces a third positively charged residue in close vicinity (Arg511, Lys507, Arg515), the protein structure seems to remain stable in the variant simulations. Importantly, according to ClinVar, the residue swap alters the last nucleotide of an exon and is predicted to destroy the splice donor site, resulting in aberrant splicing and pathogenic status. | 10.1016/j.ajhg.2020.11.011 | ||||||||||
| c.1531G>C | G511R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511R is listed in ClinVar (ID 452818.0) as Pathogenic and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain, which is treated as unavailable evidence. Overall, the majority of available predictions support a pathogenic impact, aligning with the ClinVar classification. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | Pathogenic | 1 | -11.327 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.415 | Likely Benign | 0.1307 | 0.4104 | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | -3 | -2 | -4.1 | 99.14 | 279.4 | -159.9 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | Potentially Pathogenic | Gly511 is located in an α-helix (res. Gly502-Tyr518), facing hydrophobic residues in an inter-helix space (e.g., Leu610, Ile514) in the WT simulations. In contrast, in the variant simulations, the bulkier and positively charged guanidinium side chain of Arg511 forms a salt bridge with the carboxylate group of Glu217 or hydrogen bonds with the backbone carbonyl group of Leu610. Although the residue swap introduces a third positively charged residue in close vicinity (Arg511, Lys507, Arg515), the protein structure seems to remain stable in the variant simulations. Importantly, according to ClinVar, the residue swap alters the last nucleotide of an exon and is predicted to destroy the splice donor site, resulting in aberrant splicing and pathogenic status. | 10.1016/j.ajhg.2020.11.011 | ||||||||||
| c.1532G>A | G511E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -12.263 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.479 | Likely Benign | 0.1882 | 0.4240 | 2.17 | Destabilizing | 0.2 | 2.62 | Destabilizing | 2.40 | Destabilizing | 1.15 | Destabilizing | -7.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||
| c.1532G>C | G511A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -9.621 | Likely Pathogenic | 0.844 | Likely Pathogenic | Ambiguous | 0.275 | Likely Benign | 0.3793 | 0.2778 | 0.80 | Ambiguous | 0.2 | 0.25 | Likely Benign | 0.53 | Ambiguous | 0.55 | Ambiguous | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.23 | Benign | 0.02 | Affected | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||
| c.1532G>T | G511V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511V is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no classification for G511V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -11.738 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.540 | Likely Pathogenic | 0.1557 | 0.3019 | 3.47 | Destabilizing | 0.2 | 0.79 | Ambiguous | 2.13 | Destabilizing | 0.65 | Ambiguous | -8.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.01 | Affected | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||
| c.1534G>A | E512K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512K missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, FATHMM, premPS, and Foldetta, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, seven tools predict pathogenicity versus six predicting benignity, with one uncertain result. Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -13.927 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.344 | Likely Benign | 0.2844 | 0.4776 | 0.17 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.40 | Likely Benign | -0.03 | Likely Benign | -3.85 | Deleterious | 0.962 | Probably Damaging | 0.658 | Possibly Damaging | 3.32 | Benign | 0.06 | Tolerated | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1534G>C | E512Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512Q missense change is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Because the variant is absent from ClinVar and gnomAD, there is no external evidence to contradict the computational predictions. Overall, the balance of high‑confidence tools leans toward a pathogenic interpretation, though the presence of an equal number of benign predictions indicates that the evidence remains inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -9.964 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 0.283 | Likely Benign | 0.1523 | 0.4815 | 0.09 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.26 | Likely Benign | 0.00 | Likely Benign | -2.86 | Deleterious | 0.947 | Possibly Damaging | 0.706 | Possibly Damaging | 3.32 | Benign | 0.14 | Tolerated | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||
| c.1535A>C | E512A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain results come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show SGM‑Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -10.979 | Likely Pathogenic | 0.861 | Likely Pathogenic | Ambiguous | 0.309 | Likely Benign | 0.4293 | 0.5162 | 0.45 | Likely Benign | 0.1 | 0.97 | Ambiguous | 0.71 | Ambiguous | 0.04 | Likely Benign | -5.71 | Deleterious | 0.987 | Probably Damaging | 0.937 | Probably Damaging | 3.31 | Benign | 0.12 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1535A>G | E512G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E512G is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E512G, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -11.996 | Likely Pathogenic | 0.817 | Likely Pathogenic | Ambiguous | 0.381 | Likely Benign | 0.3262 | 0.4185 | 0.86 | Ambiguous | 0.1 | 1.84 | Ambiguous | 1.35 | Ambiguous | 0.17 | Likely Benign | -6.46 | Deleterious | 0.997 | Probably Damaging | 0.915 | Probably Damaging | 3.30 | Benign | 0.02 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1535A>T | E512V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E512V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -14.011 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.439 | Likely Benign | 0.0994 | 0.4884 | 0.72 | Ambiguous | 0.1 | 1.00 | Ambiguous | 0.86 | Ambiguous | 0.14 | Likely Benign | -6.71 | Deleterious | 0.989 | Probably Damaging | 0.854 | Possibly Damaging | 3.23 | Benign | 0.01 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1536A>C | E512D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E512D is not reported in ClinVar or gnomAD. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only the ESM1b model assigns a pathogenic label, while Rosetta and Foldetta provide uncertain results. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta remains inconclusive. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -8.354 | Likely Pathogenic | 0.198 | Likely Benign | Likely Benign | 0.259 | Likely Benign | 0.2055 | 0.3089 | 0.12 | Likely Benign | 0.3 | 1.05 | Ambiguous | 0.59 | Ambiguous | 0.00 | Likely Benign | -2.10 | Neutral | 0.016 | Benign | 0.012 | Benign | 3.34 | Benign | 0.23 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1536A>T | E512D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E512D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Across the broad panel of in‑silico predictors, the majority (REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as benign, whereas only ESM1b predicts it as pathogenic. The high‑accuracy tools give a consistent benign signal: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the evidence strongly supports a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.247079 | Uncertain | 0.923 | 0.273 | 0.000 | -8.354 | Likely Pathogenic | 0.198 | Likely Benign | Likely Benign | 0.259 | Likely Benign | 0.2055 | 0.3089 | 0.12 | Likely Benign | 0.3 | 1.05 | Ambiguous | 0.59 | Ambiguous | 0.00 | Likely Benign | -2.10 | Neutral | 0.016 | Benign | 0.012 | Benign | 3.34 | Benign | 0.23 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1537T>A | F513I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513I is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely converge on a deleterious effect: SIFT is the sole benign caller, whereas REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. Grouping by consensus, the single benign prediction (SIFT) is outweighed by the 13 pathogenic calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -12.003 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.766 | Likely Pathogenic | 0.1473 | 0.1766 | 3.42 | Destabilizing | 0.4 | 2.18 | Destabilizing | 2.80 | Destabilizing | 1.12 | Destabilizing | -5.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.24 | Pathogenic | 0.22 | Tolerated | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||
| c.1537T>C | F513L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513L is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic)—all predict a deleterious effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. No evidence from FoldX or Rosetta is considered decisive. Overall, the preponderance of predictions indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.370 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.674 | Likely Pathogenic | 0.1645 | 0.2447 | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1537T>G | F513V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.675 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.799 | Likely Pathogenic | 0.1656 | 0.1583 | 3.54 | Destabilizing | 0.4 | 2.68 | Destabilizing | 3.11 | Destabilizing | 1.13 | Destabilizing | -6.70 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.21 | Pathogenic | 0.44 | Tolerated | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||
| c.1538T>A | F513Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT classifies it as benign, whereas REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict pathogenicity. Stability‑based methods (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. With 10 of 12 evaluated tools indicating pathogenicity and no conflicting ClinVar annotation, the variant is most likely pathogenic, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.022 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.791 | Likely Pathogenic | 0.1046 | 0.1087 | 1.09 | Ambiguous | 0.2 | 1.03 | Ambiguous | 1.06 | Ambiguous | 1.09 | Destabilizing | -2.92 | Deleterious | 0.988 | Probably Damaging | 0.976 | Probably Damaging | -1.39 | Pathogenic | 0.07 | Tolerated | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||
| c.1538T>C | F513S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -12.172 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.917 | Likely Pathogenic | 0.3864 | 0.0200 | 4.21 | Destabilizing | 0.4 | 4.43 | Destabilizing | 4.32 | Destabilizing | 2.25 | Destabilizing | -7.75 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.27 | Pathogenic | 0.10 | Tolerated | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||
| c.1538T>G | F513C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -11.389 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.919 | Likely Pathogenic | 0.2384 | 0.0783 | 3.92 | Destabilizing | 0.3 | 4.20 | Destabilizing | 4.06 | Destabilizing | 1.64 | Destabilizing | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.40 | Pathogenic | 0.03 | Affected | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||
| c.1539C>A | F513L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F513L is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic)—all predict a deleterious effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. No evidence from FoldX or Rosetta is considered decisive. Overall, the preponderance of predictions indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.370 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.537 | Likely Pathogenic | 0.1645 | 0.2447 | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.1539C>G | F513L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F513L missense variant has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and the Foldetta stability analysis is inconclusive and therefore not considered evidence. FoldX and Rosetta predictions are uncertain and treated as unavailable. Overall, the preponderance of evidence indicates that F513L is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.250651 | Uncertain | 0.949 | 0.269 | 0.000 | -10.370 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.537 | Likely Pathogenic | 0.1645 | 0.2447 | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||
| c.153C>G | I51M 2D AIThe SynGAP1 missense variant I51M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic call comes from SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as likely benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the I51M substitution is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.454181 | Uncertain | 0.606 | 0.710 | 0.000 | -4.732 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.093 | Likely Benign | 0.0764 | 0.3281 | -0.27 | Neutral | 0.099 | Benign | 0.075 | Benign | 4.13 | Benign | 0.00 | Affected | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.1540A>C | I514L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools (premPS and AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts a benign outcome. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -10.239 | Likely Pathogenic | 0.490 | Ambiguous | Likely Benign | 0.310 | Likely Benign | 0.0767 | 0.2678 | -0.05 | Likely Benign | 0.2 | 0.34 | Likely Benign | 0.15 | Likely Benign | 0.81 | Ambiguous | -1.99 | Neutral | 0.879 | Possibly Damaging | 0.985 | Probably Damaging | 3.31 | Benign | 0.12 | Tolerated | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||
| c.1540A>G | I514V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514V is catalogued in gnomAD (variant ID 6‑33438783‑A‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are limited to polyPhen‑2 HumDiv and HumVar. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence indicates that I514V is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | 6-33438783-A-G | 7 | 4.34e-6 | -5.187 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.173 | Likely Benign | 0.0939 | 0.2130 | 1.39 | Ambiguous | 0.0 | 0.44 | Likely Benign | 0.92 | Ambiguous | 0.89 | Ambiguous | -0.79 | Neutral | 0.914 | Possibly Damaging | 0.960 | Probably Damaging | 3.15 | Benign | 0.13 | Tolerated | 3.37 | 35 | 3 | 4 | -0.3 | -14.03 | ||||||||||||||||||||
| c.1540A>T | I514F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report it as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, classifies the variant as pathogenic. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | Uncertain | 1 | -13.383 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.601 | Likely Pathogenic | 0.0574 | 0.1629 | 2.35 | Destabilizing | 0.3 | 3.74 | Destabilizing | 3.05 | Destabilizing | 0.93 | Ambiguous | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.89 | Benign | 0.00 | Affected | 3.37 | 35 | 0 | 1 | -1.7 | 34.02 | |||||||||||||||||||||
| c.1541T>A | I514N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the overwhelming consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -13.869 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.582 | Likely Pathogenic | 0.0770 | 0.0142 | 3.41 | Destabilizing | 0.3 | 2.41 | Destabilizing | 2.91 | Destabilizing | 2.61 | Destabilizing | -6.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||
| c.1541T>C | I514T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514T has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. Rosetta reports an uncertain outcome and is not included in the consensus groups. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Taken together, the evidence overwhelmingly points to a pathogenic effect, and this conclusion is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -8.820 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.617 | Likely Pathogenic | 0.0962 | 0.0480 | 2.92 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.40 | Destabilizing | 1.94 | Destabilizing | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||
| c.1541T>G | I514S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -12.512 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.625 | Likely Pathogenic | 0.2296 | 0.0530 | 4.03 | Destabilizing | 0.2 | 3.70 | Destabilizing | 3.87 | Destabilizing | 2.11 | Destabilizing | -5.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||
| c.1542C>G | I514M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I514M is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus (majority of the four high‑accuracy inputs) remains Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is Uncertain. Overall, seven of the twelve evaluated tools predict pathogenicity versus four predicting benign, with no evidence from ClinVar to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.221408 | Uncertain | 0.948 | 0.266 | 0.000 | -9.753 | Likely Pathogenic | 0.727 | Likely Pathogenic | Likely Benign | 0.335 | Likely Benign | 0.0647 | 0.1816 | 0.48 | Likely Benign | 0.2 | 0.78 | Ambiguous | 0.63 | Ambiguous | 1.13 | Destabilizing | -2.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||
| c.1543C>A | R515S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R515S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on benign impact include only SIFT, while the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the four pathogenic‑predicted tools) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Other stability‑based predictions (FoldX, Rosetta, premPS) are also uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -10.615 | Likely Pathogenic | 0.928 | Likely Pathogenic | Ambiguous | 0.586 | Likely Pathogenic | 0.2707 | 0.1849 | 1.54 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.33 | Ambiguous | 0.92 | Ambiguous | -3.03 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.28 | Pathogenic | 0.17 | Tolerated | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||
| c.1543C>G | R515G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach consensus classify the change as pathogenic: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a deleterious effect. Tools with inconclusive results—Rosetta, Foldetta, and AlphaMissense‑Optimized—do not provide evidence for benignity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the overwhelming majority of predictions support a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -11.562 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 0.674 | Likely Pathogenic | 0.2920 | 0.1998 | 2.07 | Destabilizing | 0.3 | 1.87 | Ambiguous | 1.97 | Ambiguous | 1.29 | Destabilizing | -4.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.34 | Pathogenic | 0.04 | Affected | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||
| c.1543C>T | R515C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R515C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (6‑33438786‑C‑T). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—SGM Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | 6-33438786-C-T | 1 | 6.20e-7 | -10.973 | Likely Pathogenic | 0.628 | Likely Pathogenic | Likely Benign | 0.691 | Likely Pathogenic | 0.3055 | 0.1546 | 1.00 | Ambiguous | 0.0 | 1.13 | Ambiguous | 1.07 | Ambiguous | 0.72 | Ambiguous | -5.49 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 3.37 | 35 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||
| c.1544G>A | R515H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515H is listed in ClinVar with an uncertain significance (ClinVar ID 638438.0) and is present in gnomAD (variant ID 6‑33438787‑G‑A). Prediction tools that agree on a benign effect include AlphaMissense‑Default and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the balance of evidence favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | Uncertain | 1 | 6-33438787-G-A | 3 | 1.86e-6 | -10.774 | Likely Pathogenic | 0.337 | Likely Benign | Likely Benign | 0.730 | Likely Pathogenic | 0.2343 | 0.0746 | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 2 | 0 | 1.3 | -19.05 | 239.2 | 77.8 | 0.0 | 0.0 | 0.4 | 0.2 | X | Potentially Benign | The guanidinium group of Arg515, located in the middle of an α-helix at the GAP domain (res. Gly502-Tyr518), forms salt bridges with the carboxylate groups of Glu512 on the same helix and Glu217 on a loop in the PH domain. Additionally, the positively charged Arg515 side chain forms hydrogen bonds with Leu610 and Gln612 in an opposing loop (res. Gly609-Asp616). In contrast, in the variant simulations, the imidazole ring of His515 cannot form salt bridges with either of the acidic residues, and its side chain is too short to form hydrogen bonds with the loop residues. Accordingly, the residue swap could weaken the tertiary structure assembly of the protein. Due to the missing N-terminal part of the SynGAP model, the effect could be largely underestimated or missing. Notably, the doubly protonated and positively charged form of histidine was not simulated here. | |||||||||
| c.1544G>C | R515P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515P has no ClinVar entry and is absent from gnomAD. In silico prediction tools uniformly indicate a deleterious effect: benign‑predicting algorithms are not reported, while pathogenic‑predicting tools—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all classify the substitution as pathogenic. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -14.291 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.823 | Likely Pathogenic | 0.2223 | 0.2725 | 3.69 | Destabilizing | 0.1 | 8.87 | Destabilizing | 6.28 | Destabilizing | 1.02 | Destabilizing | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1544G>T | R515L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R515L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; FoldX and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | -10.738 | Likely Pathogenic | 0.744 | Likely Pathogenic | Likely Benign | 0.686 | Likely Pathogenic | 0.1666 | 0.2857 | 0.71 | Ambiguous | 0.2 | -0.33 | Likely Benign | 0.19 | Likely Benign | 0.52 | Ambiguous | -4.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.26 | Pathogenic | 0.11 | Tolerated | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||
| c.1546G>A | A516T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516T is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include SIFT, Rosetta, and Foldetta, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as benign. With the pathogenic predictions outweighing the benign ones, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -9.716 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.520 | Likely Pathogenic | 0.1586 | 0.5739 | 0.57 | Ambiguous | 0.2 | -0.14 | Likely Benign | 0.22 | Likely Benign | 0.63 | Ambiguous | -3.21 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | -1.29 | Pathogenic | 0.17 | Tolerated | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||
| c.1546G>C | A516P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact; premPS is inconclusive. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized scores it as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies it as pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -15.348 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.750 | Likely Pathogenic | 0.2214 | 0.4328 | 2.67 | Destabilizing | 0.3 | 10.96 | Destabilizing | 6.82 | Destabilizing | 0.83 | Ambiguous | -4.41 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.29 | Pathogenic | 0.06 | Tolerated | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1546G>T | A516S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A516S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools remain uncertain: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -9.639 | Likely Pathogenic | 0.562 | Ambiguous | Likely Benign | 0.448 | Likely Benign | 0.2730 | 0.4730 | 0.22 | Likely Benign | 0.2 | 0.24 | Likely Benign | 0.23 | Likely Benign | 0.52 | Ambiguous | -2.45 | Neutral | 0.973 | Probably Damaging | 0.993 | Probably Damaging | -1.24 | Pathogenic | 0.17 | Tolerated | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||
| c.1547C>A | A516D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A516D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, which scores the substitution as tolerated. In contrast, the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that A516D is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -14.621 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.725 | Likely Pathogenic | 0.1890 | 0.1679 | 0.65 | Ambiguous | 0.2 | 1.04 | Ambiguous | 0.85 | Ambiguous | 0.62 | Ambiguous | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.23 | Pathogenic | 0.15 | Tolerated | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||
| c.1547C>G | A516G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A516G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are limited to SIFT, whereas the remaining seven tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No stability‑change predictions are definitive. Overall, the majority of evidence points to a pathogenic impact for A516G. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -10.673 | Likely Pathogenic | 0.864 | Likely Pathogenic | Ambiguous | 0.557 | Likely Pathogenic | 0.2379 | 0.4370 | 0.86 | Ambiguous | 0.2 | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.88 | Ambiguous | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.10 | Tolerated | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1547C>T | A516V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A516V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect fall into two groups: benign predictions come from FoldX, Rosetta, and SIFT, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of tools, including the high‑accuracy predictors, lean toward a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.167423 | Uncertain | 0.938 | 0.284 | 0.000 | -11.545 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.639 | Likely Pathogenic | 0.1336 | 0.5263 | 0.42 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.29 | Likely Benign | 0.62 | Ambiguous | -3.61 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.32 | Pathogenic | 0.09 | Tolerated | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.1549C>A | L517M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Benign predictions are provided by FoldX and PROVEAN. High‑accuracy assessments are mixed: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, whereas AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No evidence from ClinVar contradicts these findings. Overall, the preponderance of evidence supports a pathogenic classification for L517M, with no conflict from existing database annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -11.613 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 0.665 | Likely Pathogenic | 0.0775 | 0.2558 | 0.38 | Likely Benign | 0.2 | 1.22 | Ambiguous | 0.80 | Ambiguous | 0.93 | Ambiguous | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||
| c.1549C>G | L517V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the change is deleterious: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM, while benign predictions are made by SIFT and AlphaMissense‑Optimized; the remaining tools (Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the preponderance of evidence points to a likely pathogenic effect of the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -10.691 | Likely Pathogenic | 0.498 | Ambiguous | Likely Benign | 0.577 | Likely Pathogenic | 0.1405 | 0.2398 | 2.04 | Destabilizing | 0.3 | 1.37 | Ambiguous | 1.71 | Ambiguous | 1.14 | Destabilizing | -2.68 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.26 | Pathogenic | 0.17 | Tolerated | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||
| c.154T>A | S52T 2D AIThe SynGAP1 missense variant S52T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and SIFT. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -5.731 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.1505 | 0.6751 | 0.06 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.154T>C | S52P 2D AIThe SynGAP1 missense variant S52P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict a pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign votes); and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S52P. This conclusion does not contradict ClinVar, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -10.007 | Likely Pathogenic | 0.797 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | 0.2276 | 0.5909 | -1.28 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||
| c.154T>G | S52A 2D AIThe SynGAP1 missense variant S52A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool predicting a pathogenic outcome is SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly supports a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -5.326 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.5389 | 0.5073 | Strenghten | -0.69 | Neutral | 0.140 | Benign | 0.355 | Benign | 4.17 | Benign | 0.00 | Affected | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||
| c.1550T>A | L517Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517Q is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -11.660 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.946 | Likely Pathogenic | 0.1031 | 0.0888 | 2.17 | Destabilizing | 0.1 | 2.07 | Destabilizing | 2.12 | Destabilizing | 1.87 | Destabilizing | -5.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1550T>C | L517P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517P is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -15.546 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.937 | Likely Pathogenic | 0.3570 | 0.1963 | 5.88 | Destabilizing | 0.8 | 7.96 | Destabilizing | 6.92 | Destabilizing | 1.92 | Destabilizing | -6.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1550T>G | L517R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool with an uncertain outcome is FoldX. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic, and Foldetta predicts Pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -14.761 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.936 | Likely Pathogenic | 0.1202 | 0.0688 | 1.75 | Ambiguous | 0.2 | 4.33 | Destabilizing | 3.04 | Destabilizing | 1.83 | Destabilizing | -5.79 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||
| c.1552T>A | Y518N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y518N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and Foldetta) uniformly predict a pathogenic impact. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta also predicts pathogenicity. Taken together, the overwhelming majority of evidence indicates a pathogenic effect. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.036 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.506 | Likely Pathogenic | 0.1791 | 0.0212 | 2.99 | Destabilizing | 0.8 | 1.50 | Ambiguous | 2.25 | Destabilizing | 1.29 | Destabilizing | -8.45 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.04 | Affected | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||
| c.1552T>C | Y518H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518H is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for Y518H, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | Uncertain | 1 | -9.797 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.496 | Likely Benign | 0.1927 | 0.0212 | 2.39 | Destabilizing | 0.4 | 0.82 | Ambiguous | 1.61 | Ambiguous | 1.31 | Destabilizing | -4.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||
| c.1552T>G | Y518D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.247 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.619 | Likely Pathogenic | 0.3682 | 0.0212 | 3.92 | Destabilizing | 0.9 | 2.68 | Destabilizing | 3.30 | Destabilizing | 1.36 | Destabilizing | -9.41 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.03 | Affected | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||
| c.1553A>C | Y518S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; AlphaMissense‑Optimized is uncertain; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the preponderance of evidence points to a pathogenic effect for Y518S, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -12.453 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 0.551 | Likely Pathogenic | 0.3948 | 0.1059 | 2.76 | Destabilizing | 0.8 | 2.45 | Destabilizing | 2.61 | Destabilizing | 1.61 | Destabilizing | -8.38 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.43 | Benign | 0.06 | Tolerated | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||
| c.1553A>G | Y518C 2D AIThe SynGAP1 missense variant Y518C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; and uncertain results from Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates likely pathogenic, and Foldetta predicts pathogenic folding instability. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -9.813 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.415 | Likely Benign | 0.2905 | 0.1128 | 2.99 | Destabilizing | 0.9 | 1.70 | Ambiguous | 2.35 | Destabilizing | 0.69 | Ambiguous | -8.35 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.16 | Tolerated | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||
| c.1553A>T | Y518F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 Y518F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools are uncertain: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of individual predictors (seven benign vs. four pathogenic) support a benign classification, and this does not contradict the ClinVar status, which has no entry for this variant. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -10.617 | Likely Pathogenic | 0.466 | Ambiguous | Likely Benign | 0.318 | Likely Benign | 0.2107 | 0.2230 | 0.34 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.14 | Likely Benign | 0.41 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.50 | Benign | 0.22 | Tolerated | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||
| c.1555G>A | E519K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519K missense variant is listed in gnomAD (ID 6‑33438798‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E519K, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | 6-33438798-G-A | 1 | 6.20e-7 | -13.532 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.328 | Likely Benign | 0.2545 | 0.3379 | -0.55 | Ambiguous | 0.0 | -0.60 | Ambiguous | -0.58 | Ambiguous | 0.06 | Likely Benign | -3.48 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | 3.28 | Benign | 0.03 | Affected | 3.37 | 35 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||
| c.1555G>C | E519Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -8.693 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | 0.195 | Likely Benign | 0.1394 | 0.3418 | -0.35 | Likely Benign | 0.1 | -0.14 | Likely Benign | -0.25 | Likely Benign | -0.21 | Likely Benign | -2.48 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 3.28 | Benign | 0.14 | Tolerated | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.1556A>C | E519A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519A missense variant is listed in ClinVar as Pathogenic (ClinVar ID 1029087.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, ESM1b, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain predictions from Rosetta and AlphaMissense‑Optimized are treated as unavailable. High‑accuracy results are: AlphaMissense‑Optimized – unavailable; SGM‑Consensus – Pathogenic; Foldetta – Benign. Overall, the predictions are balanced, but the high‑accuracy Foldetta result leans toward benign while the consensus leans toward pathogenic, leaving the assessment inconclusive. Based on the available predictions, the variant is most likely benign, contradicting the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | Likely Pathogenic | 1 | -8.557 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.384 | Likely Benign | 0.3544 | 0.3545 | -0.05 | Likely Benign | 0.0 | 0.55 | Ambiguous | 0.25 | Likely Benign | 0.00 | Likely Benign | -5.23 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.33 | Benign | 0.10 | Tolerated | 3.37 | 35 | 0 | -1 | 5.3 | -58.04 | 162.4 | 83.5 | -0.1 | 0.1 | -0.2 | 0.0 | X | Potentially Benign | Glu519 is located at the beginning of an α-α loop between the two α-helices (res. Gly502-Tyr518 and Ala533-Val560). In the WT simulations, the carboxylate side chain of Glu519 does not make any specific interactions. Accordingly, the Ala residue swap does not show any negative structural effects in the variant simulations. However, it should be noted that Glu519 faces the missing part of the N-terminal in the model, and thus its potential role in maintaining the tertiary structure might be de-emphasized in the current model. | ||||||||||||
| c.1556A>G | E519G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519G missense variant is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) lean toward a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.835 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.458 | Likely Benign | 0.2729 | 0.3471 | 0.22 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.57 | Ambiguous | 0.22 | Likely Benign | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.1556A>T | E519V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight the discord: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Overall, the preponderance of evidence points to a pathogenic effect for E519V. This conclusion does not conflict with ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.513 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.400 | Likely Benign | 0.0825 | 0.4369 | 0.59 | Ambiguous | 0.0 | -0.40 | Likely Benign | 0.10 | Likely Benign | 0.16 | Likely Benign | -6.33 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 3.20 | Benign | 0.00 | Affected | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||
| c.1557A>C | E519D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With seven benign predictions versus six pathogenic ones, the overall evidence slightly favors a benign classification. This conclusion does not contradict the ClinVar status, which contains no pathogenic assertion for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -8.009 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.183 | Likely Benign | 0.2088 | 0.1824 | 0.24 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.32 | Likely Benign | 0.05 | Likely Benign | -2.62 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 3.31 | Benign | 0.07 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1557A>T | E519D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E519D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of tools, including the high‑accuracy methods, lean toward a benign interpretation. This consensus does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -8.009 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.182 | Likely Benign | 0.2088 | 0.1824 | 0.24 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.32 | Likely Benign | 0.05 | Likely Benign | -2.62 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | 3.31 | Benign | 0.07 | Tolerated | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1558T>A | S520T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520T is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS and PROVEAN, while pathogenic predictions are made by SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four high‑accuracy methods were examined: AlphaMissense‑Optimized returned an uncertain result; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, was also uncertain. With three of the four high‑accuracy tools indicating pathogenicity and only two tools suggesting benign, the overall evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.432 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.565 | Likely Pathogenic | 0.1296 | 0.5199 | 0.52 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.52 | Ambiguous | 0.34 | Likely Benign | -2.41 | Neutral | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | -1.28 | Pathogenic | 0.02 | Affected | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||
| c.1558T>C | S520P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while premPS remains inconclusive. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Overall, the evidence strongly supports a pathogenic impact for S520P, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.707 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.855 | Likely Pathogenic | 0.2154 | 0.4776 | 3.72 | Destabilizing | 0.8 | 8.86 | Destabilizing | 6.29 | Destabilizing | 0.83 | Ambiguous | -4.57 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||
| c.1558T>G | S520A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S520A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized, whereas a larger group—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy consensus is split, but the pathogenic predictions dominate. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.417 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.523 | Likely Pathogenic | 0.4887 | 0.3636 | 0.03 | Likely Benign | 0.2 | 0.19 | Likely Benign | 0.11 | Likely Benign | 0.56 | Ambiguous | -2.55 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||
| c.1559C>A | S520Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of algorithms predict pathogenicity: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give inconclusive results: FoldX (Uncertain) and premPS (Uncertain). High‑accuracy assessments further support a mixed signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -13.124 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.814 | Likely Pathogenic | 0.0743 | 0.4563 | -0.93 | Ambiguous | 0.4 | 0.16 | Likely Benign | -0.39 | Likely Benign | 0.59 | Ambiguous | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||
| c.1559C>G | S520C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520C is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and ESM1b, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default; Rosetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -6.947 | Likely Benign | 0.917 | Likely Pathogenic | Ambiguous | 0.720 | Likely Pathogenic | 0.1029 | 0.4948 | 0.05 | Likely Benign | 0.2 | 0.76 | Ambiguous | 0.41 | Likely Benign | 0.53 | Ambiguous | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.1559C>T | S520F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520F is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include Rosetta, Foldetta, and premPS. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX gives an uncertain result. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.541 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.833 | Likely Pathogenic | 0.0668 | 0.4779 | -1.20 | Ambiguous | 0.4 | 0.39 | Likely Benign | -0.41 | Likely Benign | 0.25 | Likely Benign | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.36 | Pathogenic | 0.00 | Affected | 3.37 | 35 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||
| c.155C>G | S52W 2D  AIThe SynGAP1 missense variant S52W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, more tools (five) predict pathogenicity than benign (three), and no high‑accuracy consensus or folding‑stability evidence contradicts this trend. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not conflict with the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -8.649 | Likely Pathogenic | 0.909 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | 0.0580 | 0.6254 | -1.85 | Neutral | 0.986 | Probably Damaging | 0.968 | Probably Damaging | 4.05 | Benign | 0.00 | Affected | -2 | -3 | -0.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.155C>T | S52L 2D AISynGAP1 missense variant S52L is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33423564‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the collective evidence points to a likely benign effect, which does not contradict the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | Uncertain | 1 | 6-33423564-C-T | 1 | 6.20e-7 | -7.199 | In-Between | 0.688 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | 0.0991 | 0.6100 | -1.41 | Neutral | 0.829 | Possibly Damaging | 0.706 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 4.32 | 1 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| c.1561G>A | E521K 2D 3DClick to see structure in 3D Viewer AISynGAP1 E521K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. Overall, the majority of conventional tools lean toward a benign interpretation, while the high‑accuracy methods are split. Thus, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -9.596 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.379 | Likely Benign | 0.2895 | 0.6513 | -0.48 | Likely Benign | 0.2 | 0.14 | Likely Benign | -0.17 | Likely Benign | -0.10 | Likely Benign | -3.05 | Deleterious | 0.994 | Probably Damaging | 0.994 | Probably Damaging | 3.57 | Benign | 0.45 | Tolerated | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1561G>C | E521Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta predicts a benign stability change. Overall, the majority of evidence (9 benign vs. 4 pathogenic predictions) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -8.310 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | 0.262 | Likely Benign | 0.1580 | 0.6552 | -0.28 | Likely Benign | 0.2 | 0.19 | Likely Benign | -0.05 | Likely Benign | -0.06 | Likely Benign | -2.15 | Neutral | 0.992 | Probably Damaging | 0.993 | Probably Damaging | 3.30 | Benign | 0.11 | Tolerated | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.1562A>C | E521A 2D 3DClick to see structure in 3D Viewer AISynGAP1 E521A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give conflicting results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No prediction or stability result is missing. Overall, the evidence is evenly split, with six benign and six pathogenic calls, and the two high‑accuracy tools disagree. Therefore, the variant’s impact remains uncertain; it is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -8.997 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.395 | Likely Benign | 0.4041 | 0.5918 | 0.18 | Likely Benign | 0.1 | 0.40 | Likely Benign | 0.29 | Likely Benign | 0.11 | Likely Benign | -4.12 | Deleterious | 0.998 | Probably Damaging | 0.999 | Probably Damaging | 3.28 | Benign | 0.13 | Tolerated | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||
| c.1562A>G | E521G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E521G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it is a 2‑vs‑2 split and is treated as unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -6.636 | Likely Benign | 0.767 | Likely Pathogenic | Likely Benign | 0.289 | Likely Benign | 0.2932 | 0.5455 | 0.18 | Likely Benign | 0.1 | 0.58 | Ambiguous | 0.38 | Likely Benign | 0.14 | Likely Benign | -3.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.31 | Benign | 0.07 | Tolerated | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||
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