Table of SynGAP1 Isoform α2 (UniProt Q96PV0-1) Missense Variants.
| c.dna | Variant | SGM Consensus | Domain and Structure information: based on WT protein | Annotated databases | Deep learning-based pathogenicity predictions | Folding stability-based pathogenicity predictions | Sequence/structure-based pathogenicity predictions | Phase Separation | Evolutionary/physical properties | Molecular Dynamics-based analysis | DOI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Domain | IUPred2 | ANCHOR2 | AlphaFold | MobiDB | PhosphoSitePlus | ClinVar | gnomAD | ESM1b | AlphaMissense | FoldX | Rosetta | Foldetta | PremPS | REVEL | PROVEAN | PolyPhen-2 HumDiv | PolyPhen-2 HumVar | FATHMM | SIFT | PSMutPred | PAM | Physical | SASA | Normalized B-factor backbone | Normalized B-factor sidechain | SynGAP Structural Annotation | |||||||||||||||||||||||||||||||||||||||||||||
| Score | Prediction | Score | Prediction | pLDDT | disorder | disorder | LTP | HTP | KL | PTM | Clinical Status | Review | Subm. | ID | Allele count | Allele freq. | LLR score | Prediction | Pathogenicity | Class | Optimized | Average ΔΔG | Prediction | StdDev | ΔΔG | Prediction | ΔΔG | Prediction | ΔΔG | Prediction | Score | Prediction | Score | Prediction | pph2_prob | Prediction | pph2_prob | Prediction | Nervous System Score | Prediction | Prediction | Status | Conservation | Sequences | IP RF | SP RF | Prediction | 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.1918A>T | T640S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640S is listed in ClinVar as Benign (ClinVar ID 2980241.0) and is present in the gnomAD database (gnomAD ID 6‑33441177‑A‑T). 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 variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | Benign | 1 | 6-33441177-A-T | 1 | 6.20e-7 | -2.371 | Likely Benign | 0.062 | Likely Benign | Likely Benign | -0.78 | Ambiguous | 0.1 | 0.43 | Likely Benign | -0.18 | Likely Benign | -0.30 | Likely Benign | 0.088 | Likely Benign | 0.92 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.60 | Benign | 0.33 | Tolerated | 3.37 | 30 | 0.3406 | 0.3484 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||
| c.1919C>A | T640N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640N 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. Only the protein‑stability predictors FoldX and Rosetta returned uncertain results, which are treated as unavailable evidence. High‑accuracy assessments corroborate the benign prediction: 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, also reports a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -4.258 | Likely Benign | 0.107 | Likely Benign | Likely Benign | -0.50 | Ambiguous | 0.2 | 0.53 | Ambiguous | 0.02 | Likely Benign | 0.03 | Likely Benign | 0.097 | Likely Benign | 0.51 | Neutral | 0.229 | Benign | 0.084 | Benign | 3.45 | Benign | 0.25 | Tolerated | 0.1518 | 0.4079 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1919C>G | T640S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, premPS, Foldetta, Rosetta, REVEL, and the SGM‑Consensus score (Likely Benign) all classify the change as tolerated. 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 predicts Benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Benign. Consequently, the variant is most likely benign, and this conclusion does not contradict 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 Benign | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -2.371 | Likely Benign | 0.062 | Likely Benign | Likely Benign | -0.78 | Ambiguous | 0.1 | 0.43 | Likely Benign | -0.18 | Likely Benign | -0.30 | Likely Benign | 0.109 | Likely Benign | 0.92 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.60 | Benign | 0.33 | Tolerated | 3.37 | 30 | 0.3406 | 0.3484 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||
| c.1919C>T | T640I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640I 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, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. The remaining tools (FoldX, Rosetta, ESM1b, AlphaMissense‑Default, and Foldetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is unavailable due to a tie, and Foldetta also yields an uncertain stability change. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -7.256 | In-Between | 0.358 | Ambiguous | Likely Benign | 0.70 | Ambiguous | 0.1 | 0.66 | Ambiguous | 0.68 | Ambiguous | 0.28 | Likely Benign | 0.193 | Likely Benign | -2.75 | Deleterious | 0.322 | Benign | 0.022 | Benign | 3.46 | Benign | 0.12 | Tolerated | 0.1030 | 0.4793 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||
| c.1852C>A | Q618K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618K is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33440904‑C‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while ESM1b is 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 a benign result; and Foldetta also predicts benign stability. No predictions or folding stability results are missing or inconclusive. Based on the collective evidence, 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 | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | 6-33440904-C-A | 24 | 1.49e-5 | -7.708 | In-Between | 0.229 | Likely Benign | Likely Benign | 0.02 | Likely Benign | 0.0 | 0.16 | Likely Benign | 0.09 | Likely Benign | -0.46 | Likely Benign | 0.281 | Likely Benign | -0.05 | Neutral | 0.338 | Benign | 0.111 | Benign | -1.21 | Pathogenic | 0.29 | Tolerated | 3.37 | 35 | 0.1413 | 0.2750 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||
| c.1852C>G | Q618E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618E 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, and there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -12.535 | Likely Pathogenic | 0.162 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.48 | Likely Benign | 0.33 | Likely Benign | 0.233 | Likely Benign | -1.16 | Neutral | 0.046 | Benign | 0.021 | Benign | -1.17 | Pathogenic | 0.26 | Tolerated | 0.1003 | 0.1469 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.1853A>C | Q618P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM Consensus, ESM1b, FATHMM, PROVEAN, and Rosetta. 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 stability outputs) as uncertain. Overall, the majority of predictions lean toward a benign effect, though a subset of high‑confidence tools suggest pathogenicity. The variant’s status is not contradicted by ClinVar, which has no entry for this change. Based on the collective evidence, Q618P is most likely benign, albeit with some conflicting pathogenic signals from high‑accuracy predictors. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -8.273 | Likely Pathogenic | 0.248 | Likely Benign | Likely Benign | -0.11 | Likely Benign | 0.1 | 3.41 | Destabilizing | 1.65 | Ambiguous | 0.23 | Likely Benign | 0.449 | Likely Benign | -3.32 | Deleterious | 0.261 | Benign | 0.246 | Benign | -1.35 | Pathogenic | 0.08 | Tolerated | 0.1990 | 0.4011 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1853A>G | Q618R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618R 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, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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 | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -2.513 | Likely Benign | 0.207 | Likely Benign | Likely Benign | -0.43 | Likely Benign | 0.1 | 0.60 | Ambiguous | 0.09 | Likely Benign | -0.66 | Ambiguous | 0.285 | Likely Benign | 1.22 | Neutral | 0.005 | Benign | 0.009 | Benign | -1.24 | Pathogenic | 1.00 | Tolerated | 0.1218 | 0.1163 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1853A>T | Q618L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618L 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, premPS, SIFT, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. AlphaMissense‑Default is uncertain, whereas AlphaMissense‑Optimized predicts benign. High‑accuracy methods give the following results: AlphaMissense‑Optimized – benign; SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) – Likely Pathogenic; Foldetta – benign. Overall, the majority of tools (nine benign vs. five pathogenic) predict a benign impact. Thus, the variant is most likely benign based on current predictions, 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 | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -8.561 | Likely Pathogenic | 0.423 | Ambiguous | Likely Benign | -0.07 | Likely Benign | 0.1 | 0.20 | Likely Benign | 0.07 | Likely Benign | 0.31 | Likely Benign | 0.479 | Likely Benign | -3.94 | Deleterious | 0.712 | Possibly Damaging | 0.268 | Benign | -1.28 | Pathogenic | 0.09 | Tolerated | 0.0612 | 0.4146 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| c.1854G>C | Q618H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q618H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Four tools (FoldX, Foldetta, ESM1b, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and Foldetta is uncertain. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict the lack of ClinVar annotation or gnomAD presence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -7.092 | In-Between | 0.489 | Ambiguous | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.52 | Ambiguous | 0.34 | Likely Benign | 0.475 | Likely Benign | -1.99 | Neutral | 0.946 | Possibly Damaging | 0.638 | Possibly Damaging | -1.35 | Pathogenic | 0.04 | Affected | 0.1015 | 0.2655 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1854G>T | Q618H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q618H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Four tools (FoldX, Foldetta, ESM1b, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also uncertain. Overall, the balance of evidence leans toward a benign 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. | GAP | 0.175930 | Structured | 0.138725 | Uncertain | 0.904 | 0.240 | 0.000 | -7.092 | In-Between | 0.489 | Ambiguous | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.44 | Likely Benign | 0.52 | Ambiguous | 0.34 | Likely Benign | 0.475 | Likely Benign | -1.99 | Neutral | 0.946 | Possibly Damaging | 0.638 | Possibly Damaging | -1.35 | Pathogenic | 0.04 | Affected | 0.1015 | 0.2655 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.2041G>A | G681S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681S 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, SIFT, and FATHMM, while those that predict a pathogenic outcome are SGM‑Consensus, FoldX, 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) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of tools lean toward pathogenicity, but the presence of a benign prediction from AlphaMissense‑Optimized and an uncertain Foldetta score leaves the assessment inconclusive. No ClinVar entry exists, so there is no contradiction with clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -9.913 | Likely Pathogenic | 0.716 | Likely Pathogenic | Likely Benign | 2.11 | Destabilizing | 1.3 | -0.23 | Likely Benign | 0.94 | Ambiguous | 0.41 | Likely Benign | 0.483 | Likely Benign | -5.99 | Deleterious | 0.997 | Probably Damaging | 0.780 | Possibly Damaging | 3.45 | Benign | 0.08 | Tolerated | 0.2591 | 0.4584 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2041G>C | G681R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681R is listed in gnomAD (6-33441300-G-C) but has no ClinVar entry. In silico predictors largely converge on a deleterious effect: benign calls are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report pathogenicity. premPS is inconclusive. High‑accuracy assessments reinforce this trend: 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 pathogenic folding instability. No prediction tool suggests a benign outcome, and the variant’s presence in gnomAD does not alter the consensus. Thus, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | 6-33441300-G-C | 1 | 6.20e-7 | -12.170 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.25 | Destabilizing | 1.7 | 5.46 | Destabilizing | 3.86 | Destabilizing | 0.99 | Ambiguous | 0.556 | Likely Pathogenic | -7.98 | Deleterious | 0.999 | Probably Damaging | 0.928 | Probably Damaging | 3.42 | Benign | 0.00 | Affected | 3.43 | 14 | 0.1022 | 0.3879 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||
| c.2041G>T | G681C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681C is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all classify it as pathogenic, while only FATHMM predicts a benign outcome. Uncertain calls come from FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, Foldetta (combining FoldX‑MD and Rosetta) is pathogenic, and AlphaMissense‑Optimized remains inconclusive. Overall, the evidence strongly favors a pathogenic interpretation, 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 | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -12.374 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.89 | Ambiguous | 1.3 | 2.63 | Destabilizing | 2.26 | Destabilizing | 0.66 | Ambiguous | 0.554 | Likely Pathogenic | -8.98 | Deleterious | 1.000 | Probably Damaging | 0.959 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.1194 | 0.3886 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.2042G>A | G681D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681D 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, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all predict pathogenicity. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized returns a pathogenic classification; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. premPS is inconclusive and is treated as unavailable. Taken together, the overwhelming majority of evidence points to a pathogenic impact for G681D. 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 | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -12.451 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 2.62 | Destabilizing | 1.5 | 4.54 | Destabilizing | 3.58 | Destabilizing | 0.96 | Ambiguous | 0.471 | Likely Benign | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.840 | Possibly Damaging | 3.45 | Benign | 0.00 | Affected | 0.1697 | 0.1695 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.2042G>C | G681A 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G681A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, polyPhen‑2 HumVar, SIFT, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Predictions labeled uncertain include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. 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, reports the variant as likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for G681A. 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 | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -11.958 | Likely Pathogenic | 0.836 | Likely Pathogenic | Ambiguous | 1.77 | Ambiguous | 1.0 | 0.89 | Ambiguous | 1.33 | Ambiguous | 0.68 | Ambiguous | 0.354 | Likely Benign | -5.99 | Deleterious | 0.968 | Probably Damaging | 0.427 | Benign | 3.41 | Benign | 0.07 | Tolerated | 0.3879 | 0.4401 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2042G>T | G681V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify the change as pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus predicts a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic outcome. No other high‑confidence predictions are available. Taken together, the consensus of pathogenic predictions outweighs the single benign call, indicating that G681V is most likely pathogenic. This assessment 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 | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -14.043 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 3.21 | Destabilizing | 2.0 | 6.12 | Destabilizing | 4.67 | Destabilizing | 0.64 | Ambiguous | 0.572 | Likely Pathogenic | -8.98 | Deleterious | 0.999 | Probably Damaging | 0.928 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0.1350 | 0.3840 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.2044T>A | Y682N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 Y682N 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, while the majority of tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact; FoldX and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as pathogenic. Overall, the evidence strongly favors a pathogenic effect, 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 | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -11.734 | Likely Pathogenic | 0.859 | Likely Pathogenic | Ambiguous | 1.86 | Ambiguous | 0.1 | 2.22 | Destabilizing | 2.04 | Destabilizing | 1.54 | Destabilizing | 0.564 | Likely Pathogenic | -8.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.02 | Affected | 0.2354 | 0.0928 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.2044T>C | Y682H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y682H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FATHMM, whereas the majority of other in silico predictors (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict it to be pathogenic. The high‑accuracy consensus method SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. AlphaMissense‑Optimized and the protein‑folding stability predictor Foldetta both return uncertain results, and FoldX and Rosetta individually are inconclusive. Overall, the preponderance of pathogenic predictions outweighs the benign ones, indicating that Y682H is most likely pathogenic. 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. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -9.255 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 1.78 | Ambiguous | 0.0 | 0.56 | Ambiguous | 1.17 | Ambiguous | 1.23 | Destabilizing | 0.399 | Likely Benign | -4.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0.2405 | 0.0868 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.2044T>G | Y682D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The 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 (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. With no ClinVar assertion to oppose these findings, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -15.094 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.4 | 3.06 | Destabilizing | 2.94 | Destabilizing | 0.96 | Ambiguous | 0.639 | Likely Pathogenic | -9.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | 0.4191 | 0.0760 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.2045A>C | Y682S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). 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 uncertain. Overall, the preponderance of evidence points to a pathogenic effect for Y682S, 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 | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -11.058 | Likely Pathogenic | 0.894 | Likely Pathogenic | Ambiguous | 2.12 | Destabilizing | 0.1 | 1.12 | Ambiguous | 1.62 | Ambiguous | 0.88 | Ambiguous | 0.552 | Likely Pathogenic | -8.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.42 | Benign | 0.12 | Tolerated | 0.4487 | 0.2343 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.2045A>G | Y682C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682C is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, while only FATHMM predicts a benign outcome. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments reinforce this trend: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; AlphaMissense‑Optimized is uncertain; and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic impact for Y682C. 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 | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -10.023 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 1.79 | Ambiguous | 0.1 | 1.51 | Ambiguous | 1.65 | Ambiguous | 1.11 | Destabilizing | 0.559 | Likely Pathogenic | -8.71 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0.2949 | 0.2399 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.2045A>T | Y682F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682F 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. The SGM Consensus, which is a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs. two pathogenic votes) and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta (combining FoldX‑MD and Rosetta outputs) as benign, and the SGM Consensus remains unavailable. Overall, the balance of evidence—both from general predictors and from the high‑accuracy tools—leans toward 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 | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -9.740 | Likely Pathogenic | 0.225 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.1 | -0.09 | Likely Benign | 0.06 | Likely Benign | 0.42 | Likely Benign | 0.278 | Likely Benign | -3.72 | Deleterious | 0.997 | Probably Damaging | 0.947 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 0.2452 | 0.3662 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1789T>A | F597I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597I 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 corroborate this: 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 effect. Therefore, the variant 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 | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -13.674 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 3.62 | Destabilizing | 0.9 | 2.15 | Destabilizing | 2.89 | Destabilizing | 1.45 | Destabilizing | 0.951 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -2.18 | Pathogenic | 0.01 | Affected | 0.2008 | 0.1815 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1789T>C | F597L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant F597L is listed in ClinVar with an uncertain significance (ClinVar ID 3658115.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. The high‑accuracy AlphaMissense‑Optimized score is pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for F597L, 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 | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | Uncertain | 1 | -10.173 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 2.12 | Destabilizing | 1.43 | Ambiguous | 1.20 | Destabilizing | 0.929 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -2.06 | Pathogenic | 0.13 | Tolerated | 0.2232 | 0.2596 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||
| c.1789T>G | F597V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597V 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 corroborate this: 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 effect. Therefore, the variant 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 | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -13.883 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 3.75 | Destabilizing | 0.7 | 2.02 | Destabilizing | 2.89 | Destabilizing | 1.60 | Destabilizing | 0.939 | Likely Pathogenic | -6.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -2.16 | Pathogenic | 0.01 | Affected | 0.2237 | 0.1583 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1790T>A | F597Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include ESM1b and Rosetta, whereas a majority of tools (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, PROVEAN, premPS, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F597Y. 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 | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -5.869 | Likely Benign | 0.796 | Likely Pathogenic | Ambiguous | 1.41 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.89 | Ambiguous | 1.11 | Destabilizing | 0.877 | Likely Pathogenic | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.976 | Probably Damaging | -1.99 | Pathogenic | 0.02 | Affected | 0.1471 | 0.1494 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1790T>C | F597S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597S 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 predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: 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 stability calculations, also predicts pathogenicity. All available predictions are consistent and conclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -14.943 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 0.3 | 4.90 | Destabilizing | 4.22 | Destabilizing | 2.18 | Destabilizing | 0.953 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -2.19 | Pathogenic | 0.00 | Affected | 0.4035 | 0.0200 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1790T>G | F597C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597C is reported in gnomAD (variant ID 6-33440842‑T‑G) but has no ClinVar entry. 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 in the dataset predicts a benign outcome. High‑accuracy assessments corroborate 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 stability outputs, also predicts pathogenicity. Based on the unanimous pathogenic predictions and the absence of any benign calls, 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 | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | 6-33440842-T-G | 1 | 6.19e-7 | -12.099 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.77 | Destabilizing | 0.2 | 4.17 | Destabilizing | 3.97 | Destabilizing | 1.97 | Destabilizing | 0.953 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -2.19 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.2618 | 0.0783 | -2 | -4 | -0.3 | -44.04 | ||||||||||||||||||||||||
| c.1791C>A | F597L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F597L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: the benign group contains only SIFT, while the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta are inconclusive, providing no definitive evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a damaging effect, SGM‑Consensus concurs with a likely pathogenic classification, and Foldetta remains uncertain. Taken together, the overwhelming majority of predictions indicate a pathogenic 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 Pathogenic | GAP | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -10.173 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 2.12 | Destabilizing | 1.43 | Ambiguous | 1.20 | Destabilizing | 0.879 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -2.06 | Pathogenic | 0.13 | Tolerated | 0.2232 | 0.2596 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1791C>G | F597L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F597L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: the benign group contains only SIFT, while the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta are inconclusive, providing no definitive evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a damaging effect, SGM‑Consensus concurs with a likely pathogenic classification, and Foldetta remains uncertain. Taken together, the overwhelming majority of predictions indicate a pathogenic 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 Pathogenic | GAP | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -10.173 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 2.12 | Destabilizing | 1.43 | Ambiguous | 1.20 | Destabilizing | 0.879 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -2.06 | Pathogenic | 0.13 | Tolerated | 0.2232 | 0.2596 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.2047A>C | I683L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683L 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), FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and ESM1b. Remaining methods (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results and are treated as unavailable. 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. Overall, the balance of evidence favors a benign impact for I683L, 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 | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.988 | Likely Pathogenic | 0.488 | Ambiguous | Likely Benign | 0.63 | Ambiguous | 0.1 | 0.76 | Ambiguous | 0.70 | Ambiguous | 0.69 | Ambiguous | 0.286 | Likely Benign | -2.00 | Neutral | 0.011 | Benign | 0.056 | Benign | 3.43 | Benign | 0.04 | Affected | 0.0957 | 0.3185 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2047A>G | I683V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683V is listed in ClinVar with an uncertain significance and is present in gnomAD (6‑33441306‑A‑G). Across a panel of in silico predictors, the majority indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (derived from a majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only polyPhen‑2 HumDiv classifies the change as pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote) is benign, and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is inconclusive and therefore not considered evidence. No other tool provides a pathogenic signal. Consequently, the variant is most likely benign, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | Uncertain | 1 | 6-33441306-A-G | 2 | 1.24e-6 | -7.588 | In-Between | 0.138 | Likely Benign | Likely Benign | 0.90 | Ambiguous | 0.0 | 0.60 | Ambiguous | 0.75 | Ambiguous | 0.76 | Ambiguous | 0.112 | Likely Benign | -0.78 | Neutral | 0.538 | Possibly Damaging | 0.080 | Benign | 3.35 | Benign | 0.14 | Tolerated | 3.42 | 17 | 0.1021 | 0.2898 | 4 | 3 | -0.3 | -14.03 | 215.6 | 29.1 | 0.0 | 0.0 | -0.7 | 0.1 | X | Potentially Benign | The sec-butyl side chain of Ile683, located in an entangled α-α loop connecting the two α-helices (res. Ser641-Glu666 and res. Leu685-Val699), is sterically packed against His453 and Glu688. In the variant simulations, the iso-propyl side chain of Val683 has similar size and physicochemical properties as Ile630 in the WT, and thus, it is able to maintain similar interactions in the inter-helix space. Consequently, no negative structural effects are observed during the simulations due to the residue swap. | |||||||||||||
| c.2047A>T | I683F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683F 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, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, while AlphaMissense‑Optimized and Foldetta are inconclusive and thus treated as unavailable evidence. Overall, the balance of evidence favors a pathogenic classification for I683F, and this assessment 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 | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.781 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 1.38 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.58 | Ambiguous | 0.59 | Ambiguous | 0.481 | Likely Benign | -3.99 | Deleterious | 0.971 | Probably Damaging | 0.499 | Possibly Damaging | 3.27 | Benign | 0.01 | Affected | 0.0770 | 0.2307 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2048T>A | I683N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683N 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 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also indicates pathogenicity. No predictions are missing or inconclusive. 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 | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.120 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 2.18 | Destabilizing | 0.1 | 2.08 | Destabilizing | 2.13 | Destabilizing | 1.46 | Destabilizing | 0.546 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0978 | 0.1133 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.2048T>C | I683T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683T has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools predict pathogenicity: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support this pattern: AlphaMissense‑Optimized classifies the variant as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic; the Foldetta stability analysis is inconclusive and therefore unavailable. Taken together, the preponderance of evidence points to a pathogenic effect for I683T. This conclusion does not contradict ClinVar status, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.891 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 1.67 | Ambiguous | 0.1 | 1.35 | Ambiguous | 1.51 | Ambiguous | 1.25 | Destabilizing | 0.548 | Likely Pathogenic | -4.77 | Deleterious | 0.999 | Probably Damaging | 0.981 | Probably Damaging | 3.29 | Benign | 0.08 | Tolerated | 0.1090 | 0.0880 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.2048T>G | I683S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683S 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 majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. No prediction or folding stability result is missing or inconclusive; all available evidence points to a deleterious effect. Based on the collective predictions, 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 | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -11.443 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 2.53 | Destabilizing | 0.2 | 1.94 | Ambiguous | 2.24 | Destabilizing | 1.35 | Destabilizing | 0.552 | Likely Pathogenic | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 3.29 | Benign | 0.05 | Affected | 0.1936 | 0.1320 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.2049C>G | I683M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I683M variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, 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, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results 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 majority of definitive predictions (five pathogenic vs. three benign) point to a pathogenic impact. 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. | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.010 | Likely Pathogenic | 0.424 | Ambiguous | Likely Benign | 0.69 | Ambiguous | 0.1 | 0.68 | Ambiguous | 0.69 | Ambiguous | 0.74 | Ambiguous | 0.296 | Likely Benign | -2.88 | Deleterious | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.0933 | 0.2662 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| 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 | 0.38 | Likely Benign | 0.2 | 1.22 | Ambiguous | 0.80 | Ambiguous | 0.93 | Ambiguous | 0.665 | Likely Pathogenic | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.0775 | 0.2558 | 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 | 2.04 | Destabilizing | 0.3 | 1.37 | Ambiguous | 1.71 | Ambiguous | 1.14 | Destabilizing | 0.577 | Likely Pathogenic | -2.68 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.26 | Pathogenic | 0.17 | Tolerated | 0.1405 | 0.2398 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| 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 | 2.17 | Destabilizing | 0.1 | 2.07 | Destabilizing | 2.12 | Destabilizing | 1.87 | Destabilizing | 0.946 | Likely Pathogenic | -5.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.1031 | 0.0888 | -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 | 5.88 | Destabilizing | 0.8 | 7.96 | Destabilizing | 6.92 | Destabilizing | 1.92 | Destabilizing | 0.937 | Likely Pathogenic | -6.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.3570 | 0.1963 | -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 | 1.75 | Ambiguous | 0.2 | 4.33 | Destabilizing | 3.04 | Destabilizing | 1.83 | Destabilizing | 0.936 | Likely Pathogenic | -5.79 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.1202 | 0.0688 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1792C>A | L598I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and ESM1b. The remaining tools (FoldX, 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 benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign impact. 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 | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -9.396 | Likely Pathogenic | 0.512 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.38 | Likely Benign | 0.59 | Ambiguous | 0.78 | Ambiguous | 0.246 | Likely Benign | -1.96 | Neutral | 0.988 | Probably Damaging | 0.910 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 0.0792 | 0.2000 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1792C>G | L598V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L598V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by 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, indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as inconclusive. Overall, the majority of evidence points to 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 | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | Uncertain | 1 | -10.002 | Likely Pathogenic | 0.578 | Likely Pathogenic | Likely Benign | 1.89 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.74 | Ambiguous | 1.01 | Destabilizing | 0.221 | Likely Benign | -2.92 | Deleterious | 0.944 | Possibly Damaging | 0.786 | Possibly Damaging | 3.21 | Benign | 0.02 | Affected | 3.37 | 35 | 0.1082 | 0.1795 | 2 | 1 | 0.4 | -14.03 | 218.4 | 29.6 | 0.0 | 0.0 | 0.8 | 0.0 | X | Potentially Benign | The iso-butyl side chain of Leu598, located on an α helix (res. Glu582-Met603), packs hydrophobically with other hydrophobic residues in the inter-helix space (e.g., Ile602, Phe594, Ile510).In the variant simulations, Val598, which has similar size and physicochemical properties to leucine, resides in the inter-helix hydrophobic space in a similar manner to Leu598 in the WT. This causes no negative effects on the protein structure. | ||||||||||||||||
| c.1792C>T | L598F 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L598F is not reported in ClinVar and is absent from gnomAD. Computational predictors show mixed results: benign calls come from REVEL, Rosetta, premPS, SIFT, and FATHMM; pathogenic calls come from SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and AlphaMissense‑Optimized returned uncertain results, which are treated as unavailable evidence. High‑accuracy tools give a split view: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the balance of evidence leans toward pathogenicity, with six pathogenic versus five benign predictions and no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -10.649 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 1.12 | Ambiguous | 0.7 | -0.24 | Likely Benign | 0.44 | Likely Benign | 0.47 | Likely Benign | 0.283 | Likely Benign | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.946 | Probably Damaging | 3.62 | Benign | 0.22 | Tolerated | 0.0630 | 0.1414 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1793T>A | L598H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score; 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 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 | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -17.210 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.2 | 2.37 | Destabilizing | 2.45 | Destabilizing | 2.24 | Destabilizing | 0.648 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 0.1060 | 0.0879 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1793T>C | L598P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, 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 scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also classifies it as pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, 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 | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -12.621 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 8.31 | Destabilizing | 0.5 | 12.04 | Destabilizing | 10.18 | Destabilizing | 2.02 | Destabilizing | 0.705 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 0.2742 | 0.1192 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1793T>G | L598R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L598R 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, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. 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. 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 entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.007259 | Structured | 0.147872 | Uncertain | 0.953 | 0.154 | 0.000 | -17.392 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.70 | Destabilizing | 0.5 | 3.06 | Destabilizing | 2.88 | Destabilizing | 2.23 | Destabilizing | 0.682 | Likely Pathogenic | -5.87 | Deleterious | 0.999 | Probably Damaging | 0.973 | Probably Damaging | 3.10 | Benign | 0.00 | Affected | 0.1297 | 0.0679 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1795T>A | C599S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599S 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, which scores the variant as benign. All other evaluated algorithms—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments show the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta (combining FoldX‑MD and Rosetta) as Uncertain. No prediction or folding stability result is missing; all available data are reported. Based on the preponderance 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 | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.336 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.85 | Ambiguous | 0.0 | 1.57 | Ambiguous | 1.21 | Ambiguous | 1.27 | Destabilizing | 0.919 | Likely Pathogenic | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.45 | Pathogenic | 0.06 | Tolerated | 0.3414 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1795T>C | C599R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, PROVEAN, ESM1b, FATHMM, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic, while FoldX reports an uncertain outcome. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and 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 Pathogenic | GAP | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -15.968 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.00 | Ambiguous | 0.3 | 3.29 | Destabilizing | 2.15 | Destabilizing | 1.54 | Destabilizing | 0.909 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.1519 | 0.1566 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.1795T>G | C599G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a deleterious effect include 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). No tool predicts a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the evidence strongly favors 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 | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.342 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 1.40 | Ambiguous | 0.0 | 0.90 | Ambiguous | 1.15 | Ambiguous | 1.43 | Destabilizing | 0.923 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.03 | Affected | 0.2444 | 0.2130 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1796G>A | C599Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599Y is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include only premPS, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this assessment 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 | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.563 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.00 | Destabilizing | 1.4 | 2.80 | Destabilizing | 3.40 | Destabilizing | -0.29 | Likely Benign | 0.905 | Likely Pathogenic | -10.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.49 | Pathogenic | 0.00 | Affected | 0.1092 | 0.2555 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1796G>C | C599S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599S is not reported in ClinVar and has no entries in gnomAD. Prediction tools cluster into two groups: the sole benign prediction comes from SIFT, whereas the remaining nine tools—REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—indicate pathogenicity. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. FoldX and Rosetta individually report uncertain stability changes. Overall, the majority of evidence points to a deleterious effect, so the variant is most likely pathogenic, with no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.336 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.85 | Ambiguous | 0.0 | 1.57 | Ambiguous | 1.21 | Ambiguous | 1.27 | Destabilizing | 0.866 | Likely Pathogenic | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.45 | Pathogenic | 0.06 | Tolerated | 0.3414 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1796G>T | C599F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599F 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 prediction or folding‑stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, 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 | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -13.969 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 3.72 | Destabilizing | 1.3 | 2.70 | Destabilizing | 3.21 | Destabilizing | -0.42 | Likely Benign | 0.902 | Likely Pathogenic | -10.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.47 | Pathogenic | 0.00 | Affected | 0.1319 | 0.3073 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1797C>G | C599W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C599W 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 premPS; all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) 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, 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 | 0.009865 | Structured | 0.151725 | Uncertain | 0.960 | 0.151 | 0.000 | -17.500 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.85 | Destabilizing | 0.6 | 3.32 | Destabilizing | 3.59 | Destabilizing | 0.16 | Likely Benign | 0.715 | Likely Pathogenic | -10.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.52 | Pathogenic | 0.00 | Affected | 0.1500 | 0.2363 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.2050G>A | D684N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684N is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools predict a pathogenic outcome: 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 reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus also reports it as likely pathogenic, and the Foldetta stability analysis is inconclusive. Protein‑stability predictors FoldX and Rosetta likewise return uncertain results. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | Uncertain | 1 | -13.155 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.47 | Ambiguous | 0.8 | 1.76 | Ambiguous | 1.62 | Ambiguous | 0.37 | Likely Benign | 0.382 | Likely Benign | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.746 | Possibly Damaging | 3.39 | Benign | 0.01 | Affected | 0.1157 | 0.6373 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||
| c.2050G>C | D684H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684H is listed in ClinVar with an “Uncertain” status 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, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact, and the SGM‑Consensus score is “Likely Pathogenic.” 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 predictions are inconclusive or missing. Based on the overwhelming majority of pathogenic 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | Uncertain | 1 | -14.194 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.36 | Destabilizing | 1.0 | 2.95 | Destabilizing | 3.16 | Destabilizing | 0.55 | Ambiguous | 0.613 | Likely Pathogenic | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.972 | Probably Damaging | 3.36 | Benign | 0.00 | Affected | 3.42 | 17 | 0.1344 | 0.6618 | -1 | 1 | 0.3 | 22.05 | |||||||||||||||||||||||||
| c.2050G>T | D684Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. Only premPS and FATHMM predict a benign effect. 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 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 assessment does not contradict the absence of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -15.224 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 1.5 | 2.12 | Destabilizing | 2.89 | Destabilizing | -0.06 | Likely Benign | 0.600 | Likely Pathogenic | -8.98 | Deleterious | 1.000 | Probably Damaging | 0.963 | Probably Damaging | 3.44 | Benign | 0.00 | Affected | 0.0575 | 0.6564 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.2051A>C | D684A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only premPS and FATHMM predict a benign outcome. High‑accuracy assessments reinforce the pathogenic interpretation: 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 evidence 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.34 | Destabilizing | 1.1 | 2.85 | Destabilizing | 3.10 | Destabilizing | 0.28 | Likely Benign | 0.547 | Likely Pathogenic | -7.98 | Deleterious | 0.994 | Probably Damaging | 0.758 | Possibly Damaging | 3.42 | Benign | 0.01 | Affected | 0.3477 | 0.5423 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.2051A>G | D684G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome. Benign predictions come from premPS and FATHMM, whereas the remaining 12 tools—including REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify it 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 (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive or missing. 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.238 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.34 | Destabilizing | 1.0 | 4.07 | Destabilizing | 3.71 | Destabilizing | -0.30 | Likely Benign | 0.561 | Likely Pathogenic | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.3686 | 0.5403 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.2051A>T | D684V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only premPS and FATHMM predict a benign outcome. High‑accuracy assessments reinforce the pathogenic interpretation: 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 evidence suggests a benign effect, and the lack of ClinVar annotation means there is no conflicting clinical classification. Therefore, 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -16.128 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.86 | Destabilizing | 1.1 | 2.06 | Destabilizing | 2.96 | Destabilizing | 0.07 | Likely Benign | 0.601 | Likely Pathogenic | -8.98 | Deleterious | 0.901 | Possibly Damaging | 0.480 | Possibly Damaging | 3.44 | Benign | 0.00 | Affected | 0.0775 | 0.6209 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.2052C>A | D684E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D684E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, a majority of predictors (SGM‑Consensus, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; predictions from Rosetta and premPS are inconclusive and are treated as unavailable. 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 consensus of 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -9.506 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.18 | Destabilizing | 0.66 | Ambiguous | 0.362 | Likely Benign | -3.99 | Deleterious | 0.910 | Possibly Damaging | 0.210 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1316 | 0.6187 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2052C>G | D684E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684E is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of algorithms predict a deleterious effect: FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Two methods (Rosetta and premPS) returned uncertain results. High‑accuracy assessments further support a damaging 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) is pathogenic. Overall, the computational evidence overwhelmingly indicates that D684E is 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 | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -9.506 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.18 | Destabilizing | 0.66 | Ambiguous | 0.362 | Likely Benign | -3.99 | Deleterious | 0.910 | Possibly Damaging | 0.210 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1316 | 0.6187 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1975T>A | S659T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign. Only Rosetta reports an uncertain outcome, which is treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -5.693 | Likely Benign | 0.157 | Likely Benign | Likely Benign | -0.15 | Likely Benign | 0.0 | -0.74 | Ambiguous | -0.45 | Likely Benign | 0.42 | Likely Benign | 0.106 | Likely Benign | -2.04 | Neutral | 0.069 | Benign | 0.011 | Benign | 3.41 | Benign | 0.39 | Tolerated | 0.1505 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1975T>C | S659P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are SGM‑Consensus, Rosetta, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, premPS, and Foldetta—are treated as unavailable. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized reports a benign change, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta’s stability assessment is uncertain. Overall, the balance of evidence leans toward a pathogenic effect, but the presence of a strong benign prediction from AlphaMissense‑Optimized and the lack of ClinVar annotation means the variant’s clinical significance remains uncertain and does not contradict existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -10.461 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | -0.73 | Ambiguous | 0.3 | 2.98 | Destabilizing | 1.13 | Ambiguous | 0.73 | Ambiguous | 0.224 | Likely Benign | -3.26 | Deleterious | 0.932 | Possibly Damaging | 0.245 | Benign | 3.39 | Benign | 0.18 | Tolerated | 0.2207 | 0.5553 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1975T>G | S659A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while ESM1b remains uncertain. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. 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 | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -7.066 | In-Between | 0.117 | Likely Benign | Likely Benign | -0.31 | Likely Benign | 0.0 | 0.02 | Likely Benign | -0.15 | Likely Benign | 0.14 | Likely Benign | 0.088 | Likely Benign | -2.22 | Neutral | 0.097 | Benign | 0.114 | Benign | 3.50 | Benign | 0.64 | Tolerated | 0.4842 | 0.3813 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1976C>A | S659Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659Y 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, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default; FoldX is uncertain and therefore not considered evidence. 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 lean toward a benign impact, and there is no ClinVar entry to contradict this assessment. 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. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -10.832 | Likely Pathogenic | 0.600 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.1 | 0.00 | Likely Benign | -0.32 | Likely Benign | 0.29 | Likely Benign | 0.173 | Likely Benign | -4.24 | Deleterious | 0.084 | Benign | 0.014 | Benign | 3.38 | Benign | 0.04 | Affected | 0.0993 | 0.5962 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.1976C>G | S659C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659C 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. Two tools (Rosetta and ESM1b) return uncertain results and are not counted as evidence for either side. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Based on the collective predictions, 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. | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -7.133 | In-Between | 0.161 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.0 | 0.69 | Ambiguous | 0.39 | Likely Benign | 0.36 | Likely Benign | 0.173 | Likely Benign | -4.12 | Deleterious | 0.981 | Probably Damaging | 0.397 | Benign | 3.36 | Benign | 0.04 | Affected | 0.1130 | 0.5384 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.1976C>T | S659F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659F is listed in ClinVar with an uncertain significance and is absent from gnomAD. Functional prediction tools that provide definitive calls cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, polyPhen2_HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, SGM Consensus predicts pathogenic, and Foldetta (which integrates FoldX‑MD and Rosetta outputs) yields an uncertain result and is therefore unavailable. Overall, the majority of reliable tools favor a pathogenic effect. Thus, the variant is most likely pathogenic, a conclusion that does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | Uncertain | 1 | -10.925 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | -0.81 | Ambiguous | 0.1 | -0.25 | Likely Benign | -0.53 | Ambiguous | 0.32 | Likely Benign | 0.194 | Likely Benign | -4.59 | Deleterious | 0.806 | Possibly Damaging | 0.171 | Benign | 3.39 | Benign | 0.05 | Affected | 3.38 | 28 | 0.0897 | 0.5828 | -3 | -2 | 3.6 | 60.10 | 221.3 | -61.2 | 0.0 | 0.0 | 0.6 | 0.4 | X | Potentially Benign | In the WT simulations, the hydroxyl group of Ser659, located in a kink in the middle of the long α-helix (res. Ser641-Glu666), forms a hydrogen bond with the carboxylate group of Glu656. However, the phenol ring of the Phe659 side chain cannot form a similar hydrogen bond. Instead, it interacts with the hydrophobic isopropyl side chain of Val555 from the opposing α-helix (res. Ala533-Val560). This residue swap may therefore cause issues during protein folding. | ||||||||||||||||
| c.1849G>A | E617K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617K is not reported in ClinVar but is present in gnomAD (6‑33440901‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and SIFT, while pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. A third set of methods (Foldetta, AlphaMissense‑Optimized, Rosetta) yield uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect for E617K, 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 | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | 6-33440901-G-A | 1 | 6.20e-7 | -10.702 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.37 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.78 | Ambiguous | 0.17 | Likely Benign | 0.534 | Likely Pathogenic | -3.32 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | -1.34 | Pathogenic | 0.48 | Tolerated | 3.37 | 35 | 0.1981 | 0.6282 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.1849G>C | E617Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E617Q missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those 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). Foldetta and Rosetta give uncertain results, which are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority of high‑confidence predictors) indicates a likely pathogenic outcome. Foldetta’s stability prediction is inconclusive. Overall, the balance of evidence leans toward a pathogenic impact for E617Q, 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 | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -8.650 | Likely Pathogenic | 0.747 | Likely Pathogenic | Likely Benign | 0.20 | Likely Benign | 0.2 | 1.01 | Ambiguous | 0.61 | Ambiguous | 0.21 | Likely Benign | 0.481 | Likely Benign | -2.39 | Neutral | 0.996 | Probably Damaging | 0.986 | Probably Damaging | -1.39 | Pathogenic | 0.29 | Tolerated | 0.1050 | 0.5951 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1850A>C | E617A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617A 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, premPS, 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; Rosetta and Foldetta are uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta remains 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. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -8.704 | Likely Pathogenic | 0.769 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.1 | 0.89 | Ambiguous | 0.63 | Ambiguous | 0.18 | Likely Benign | 0.627 | Likely Pathogenic | -4.75 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.37 | Pathogenic | 0.46 | Tolerated | 0.3033 | 0.5317 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1850A>G | E617G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and ESM1b. 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 is 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 | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -7.984 | In-Between | 0.777 | Likely Pathogenic | Likely Benign | 0.59 | Ambiguous | 0.2 | 1.60 | Ambiguous | 1.10 | Ambiguous | 0.22 | Likely Benign | 0.701 | Likely Pathogenic | -4.99 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.18 | Tolerated | 0.2344 | 0.5442 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1850A>T | E617V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617V has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign (premPS, SIFT) and pathogenic (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default). Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments reinforce the pathogenic signal: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic, while AlphaMissense‑Optimized remains uncertain and Foldetta is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E617V. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -10.826 | Likely Pathogenic | 0.907 | Likely Pathogenic | Ambiguous | 0.60 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.76 | Ambiguous | 0.28 | Likely Benign | 0.816 | Likely Pathogenic | -5.71 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | -1.47 | Pathogenic | 0.13 | Tolerated | 0.0587 | 0.6503 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1851G>C | E617D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change E617D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a benign effect. Based on the preponderance of evidence from both general and high‑accuracy predictors, 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 | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | -1.349 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.46 | Likely Benign | 0.07 | Likely Benign | 0.322 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.35 | Pathogenic | 0.88 | Tolerated | 3.37 | 35 | 0.1854 | 0.3386 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.1851G>T | E617D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E617D is listed in ClinVar with an uncertain significance (ID 2584916.0) and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score all indicate benign or likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact, while Rosetta remains inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence supports a benign classification, which does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.111485 | Structured | 0.155123 | Uncertain | 0.877 | 0.240 | 0.000 | Uncertain | 1 | -1.349 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.46 | Likely Benign | 0.07 | Likely Benign | 0.322 | Likely Benign | -0.01 | Neutral | 0.994 | Probably Damaging | 0.979 | Probably Damaging | -1.35 | Pathogenic | 0.88 | Tolerated | 3.37 | 35 | 0.1854 | 0.3386 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||
| c.1921T>A | S641T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641T 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 score the variant as benign. Rosetta also predicts a benign outcome, while FoldX and Foldetta are inconclusive (marked “Uncertain”). No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta remains uncertain. Consequently, the variant is most likely benign, 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 Benign | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.637 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.3 | 0.41 | Likely Benign | 0.62 | Ambiguous | 0.13 | Likely Benign | 0.043 | Likely Benign | -1.50 | Neutral | 0.008 | Benign | 0.003 | Benign | 3.39 | Benign | 0.09 | Tolerated | 0.1505 | 0.5888 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1921T>C | S641P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and SIFT. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate 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 | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.907 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 1.73 | Ambiguous | 1.3 | 0.07 | Likely Benign | 0.90 | Ambiguous | 0.59 | Ambiguous | 0.205 | Likely Benign | -3.05 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.34 | Benign | 0.04 | Affected | 0.2289 | 0.5791 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.1921T>G | S641A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641A is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. Consequently, the variant is most likely benign based on current predictions, 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 Benign | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.103 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.2 | -0.28 | Likely Benign | 0.05 | Likely Benign | 0.27 | Likely Benign | 0.067 | Likely Benign | -2.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.43 | Benign | 0.17 | Tolerated | 0.4873 | 0.4680 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1922C>T | S641L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and ESM1b. 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 because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -9.501 | Likely Pathogenic | 0.237 | Likely Benign | Likely Benign | 0.33 | Likely Benign | 0.3 | -0.14 | Likely Benign | 0.10 | Likely Benign | 0.32 | Likely Benign | 0.103 | Likely Benign | -4.33 | Deleterious | 0.115 | Benign | 0.014 | Benign | 3.39 | Benign | 0.07 | Tolerated | 0.1248 | 0.5376 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||
| c.2053T>A | L685M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from premPS, Foldetta, Rosetta, and AlphaMissense‑Optimized. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑to‑2 tie and therefore uncertain; Foldetta also reports an uncertain stability change. Consequently, the overall computational evidence is mixed, with a slight tilt toward pathogenicity. Thus, the variant is most likely pathogenic based on predictions, 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -10.790 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.35 | Likely Benign | 0.1 | 1.01 | Ambiguous | 0.68 | Ambiguous | 0.83 | Ambiguous | 0.281 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.29 | Benign | 0.01 | Affected | 0.0814 | 0.2758 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2053T>G | L685V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685V 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, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability methods provide definitive evidence. Overall, the preponderance of pathogenic predictions, including the SGM Consensus, suggests that the variant is most likely pathogenic; 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 | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -11.418 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.87 | Ambiguous | 0.0 | 1.15 | Ambiguous | 1.51 | Ambiguous | 0.97 | Ambiguous | 0.214 | Likely Benign | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.694 | Possibly Damaging | 3.33 | Benign | 0.02 | Affected | 0.1414 | 0.3010 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2054T>C | L685S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685S 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, 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, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.303 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.08 | Destabilizing | 0.2 | 2.95 | Destabilizing | 3.02 | Destabilizing | 1.24 | Destabilizing | 0.520 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.2844 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.2054T>G | L685W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685W 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, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -15.885 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.53 | Ambiguous | 0.2 | 1.14 | Ambiguous | 1.34 | Ambiguous | 1.14 | Destabilizing | 0.509 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.0700 | 0.2328 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.2055G>C | L685F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685F is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, 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 support a deleterious effect: AlphaMissense‑Optimized classifies the change as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX and Rosetta predictions are uncertain and are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic impact for the variant, 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.304 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.62 | Ambiguous | 0.2 | 1.80 | Ambiguous | 1.71 | Ambiguous | 0.50 | Likely Benign | 0.300 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.33 | Benign | 0.01 | Affected | 0.0724 | 0.2367 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2055G>T | L685F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685F is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, 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 support a deleterious effect: AlphaMissense‑Optimized classifies the change as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX and Rosetta predictions are uncertain and are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic impact for the variant, 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 | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.304 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.62 | Ambiguous | 0.2 | 1.80 | Ambiguous | 1.71 | Ambiguous | 0.50 | Likely Benign | 0.300 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.33 | Benign | 0.01 | Affected | 0.0724 | 0.2367 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1798C>A | P600T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, Rosetta, and premPS. Those that predict pathogenicity are REVEL, 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, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, while Foldetta indicates a benign effect on protein folding stability. Overall, the majority of computational evidence supports a pathogenic effect for P600T, 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 | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -11.945 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.61 | Destabilizing | 0.1 | -2.90 | Stabilizing | -0.15 | Likely Benign | 0.24 | Likely Benign | 0.737 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.34 | Pathogenic | 0.01 | Affected | 0.1871 | 0.4954 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.1798C>G | P600A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from Rosetta and premPS, while the remaining 11 tools (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM Consensus) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain result. Taken together, the overwhelming majority of evidence indicates that P600A 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 | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -11.385 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.0 | -3.30 | Stabilizing | -0.57 | Ambiguous | 0.39 | Likely Benign | 0.581 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.38 | Pathogenic | 0.03 | Affected | 0.3692 | 0.4132 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1798C>T | P600S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of other in‑silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict it to be pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as benign. No contradictory evidence exists in ClinVar. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -12.002 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.54 | Destabilizing | 0.1 | -2.60 | Stabilizing | -0.03 | Likely Benign | 0.52 | Ambiguous | 0.717 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.40 | Pathogenic | 0.01 | Affected | 0.3744 | 0.4200 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1799C>A | P600Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions are limited to Rosetta, whereas the remaining tools—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)—all classify the variant as pathogenic. Uncertain results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence indicates that P600Q is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -14.187 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.76 | Ambiguous | 0.0 | -3.09 | Stabilizing | -0.67 | Ambiguous | 0.53 | Ambiguous | 0.739 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.34 | Pathogenic | 0.00 | Affected | 0.1740 | 0.3970 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||
| c.1799C>G | P600R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome; FoldX and Foldetta are inconclusive. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the computational evidence strongly favors a pathogenic classification, and this does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -15.304 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.48 | Ambiguous | 0.1 | -2.48 | Stabilizing | -0.50 | Ambiguous | 0.37 | Likely Benign | 0.756 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.34 | Pathogenic | 0.00 | Affected | 0.1604 | 0.2734 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1799C>T | P600L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600L is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. FoldX and Foldetta give uncertain results. High‑accuracy methods specifically show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P600L, 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 | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -13.209 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.36 | Ambiguous | 0.1 | -3.58 | Stabilizing | -1.11 | Ambiguous | -0.49 | Likely Benign | 0.734 | Likely Pathogenic | -9.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.35 | Pathogenic | 0.00 | Affected | 0.2391 | 0.5555 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.1846G>A | D616N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616N missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into benign (REVEL, premPS, SIFT, FATHMM, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b). Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) favors pathogenic, and Foldetta remains uncertain. Overall, the majority of conventional predictors lean toward a benign effect, whereas the SGM Consensus suggests pathogenicity, leaving the variant’s clinical significance ambiguous. Based on the prevailing evidence, 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 | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -8.292 | Likely Pathogenic | 0.349 | Ambiguous | Likely Benign | 0.54 | Ambiguous | 0.2 | 1.05 | Ambiguous | 0.80 | Ambiguous | 0.03 | Likely Benign | 0.149 | Likely Benign | -3.74 | Deleterious | 0.875 | Possibly Damaging | 0.581 | Possibly Damaging | 3.41 | Benign | 0.11 | Tolerated | 0.1053 | 0.3976 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1846G>C | D616H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616H 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, premPS, and FATHMM. Those that agree on a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results—Rosetta and AlphaMissense‑Optimized—so their outputs are treated as unavailable for inference. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is Pathogenic. Overall, the majority of evidence points to a pathogenic effect. The variant’s predicted pathogenicity 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 | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -9.815 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 2.13 | Destabilizing | 0.2 | 1.89 | Ambiguous | 2.01 | Destabilizing | 0.45 | Likely Benign | 0.316 | Likely Benign | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.952 | Probably Damaging | 3.30 | Benign | 0.03 | Affected | 0.1330 | 0.4273 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1846G>T | D616Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D616Y 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, whereas a majority of tools predict a pathogenic outcome: SIFT, 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, also classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -12.638 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.51 | Ambiguous | 0.35 | Likely Benign | 0.374 | Likely Benign | -7.43 | Deleterious | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.0465 | 0.4069 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1847A>C | D616A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616A missense variant 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 (Likely Pathogenic), Rosetta, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as benign, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -11.386 | Likely Pathogenic | 0.664 | Likely Pathogenic | Likely Benign | 1.76 | Ambiguous | 0.2 | 2.07 | Destabilizing | 1.92 | Ambiguous | 0.41 | Likely Benign | 0.126 | Likely Benign | -6.13 | Deleterious | 0.539 | Possibly Damaging | 0.122 | Benign | 3.32 | Benign | 0.10 | Tolerated | 0.3543 | 0.4207 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1847A>G | D616G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616G 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results—FoldX, AlphaMissense‑Default, and Foldetta—are treated as unavailable. 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 predictions are split evenly between benign and pathogenic, with no clear consensus. Thus, the variant is most likely of uncertain significance; it does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -10.310 | Likely Pathogenic | 0.547 | Ambiguous | Likely Benign | 1.48 | Ambiguous | 0.1 | 2.13 | Destabilizing | 1.81 | Ambiguous | 0.49 | Likely Benign | 0.144 | Likely Benign | -5.60 | Deleterious | 0.985 | Probably Damaging | 0.800 | Possibly Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.3496 | 0.4386 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.1847A>T | D616V 2D 3DClick to see structure in 3D Viewer AISynGAP1 D616V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, and FATHMM, while pathogenic calls are made by FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic signal: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of evidence, including the high‑accuracy tools, supports a pathogenic effect for D616V. 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 | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -13.992 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 2.41 | Destabilizing | 0.2 | 1.95 | Ambiguous | 2.18 | Destabilizing | 0.36 | Likely Benign | 0.268 | Likely Benign | -7.36 | Deleterious | 0.972 | Probably Damaging | 0.682 | Possibly Damaging | 3.26 | Benign | 0.00 | Affected | 0.0699 | 0.4393 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1848T>A | D616E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616E missense variant is catalogued in gnomAD (ID 6‑33440900‑T‑A) but has no ClinVar submission. Functional prediction tools show a split assessment: benign calls come from REVEL, both polyPhen‑2 HumDiv and HumVar, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, SIFT, and AlphaMissense‑Default. The remaining predictors (FoldX, Rosetta, Foldetta, premPS, ESM1b) are inconclusive. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized remains benign, and Foldetta, which evaluates protein‑folding stability, is uncertain. Overall, the majority of evidence leans toward pathogenicity, and this conclusion does not conflict with ClinVar because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | 6-33440900-T-A | 1 | 6.20e-7 | -7.250 | In-Between | 0.695 | Likely Pathogenic | Likely Benign | 0.96 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.24 | Ambiguous | 0.58 | Ambiguous | 0.092 | Likely Benign | -2.85 | Deleterious | 0.421 | Benign | 0.232 | Benign | 3.32 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1225 | 0.4128 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1848T>G | D616E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D616E is not reported in ClinVar but is present in gnomAD (ID 6‑33440900‑T‑G). Functional prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, SIFT, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) 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 uncertain. Overall, the majority of conventional predictors lean toward a benign effect, but the high‑accuracy consensus is split, leaving the variant’s clinical significance unresolved. Thus, the variant is most likely benign based on the bulk of predictions, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | 6-33440900-T-G | 3 | 1.86e-6 | -7.250 | In-Between | 0.695 | Likely Pathogenic | Likely Benign | 0.96 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.24 | Ambiguous | 0.58 | Ambiguous | 0.092 | Likely Benign | -2.85 | Deleterious | 0.421 | Benign | 0.232 | Benign | 3.32 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1225 | 0.4128 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||
| 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 | 0.57 | Ambiguous | 0.2 | -0.14 | Likely Benign | 0.22 | Likely Benign | 0.63 | Ambiguous | 0.520 | Likely Pathogenic | -3.21 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | -1.29 | Pathogenic | 0.17 | Tolerated | 0.1586 | 0.5739 | 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 | 2.67 | Destabilizing | 0.3 | 10.96 | Destabilizing | 6.82 | Destabilizing | 0.83 | Ambiguous | 0.750 | Likely Pathogenic | -4.41 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.29 | Pathogenic | 0.06 | Tolerated | 0.2214 | 0.4328 | 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 | 0.22 | Likely Benign | 0.2 | 0.24 | Likely Benign | 0.23 | Likely Benign | 0.52 | Ambiguous | 0.448 | Likely Benign | -2.45 | Neutral | 0.973 | Probably Damaging | 0.993 | Probably Damaging | -1.24 | Pathogenic | 0.17 | Tolerated | 0.2730 | 0.4730 | 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 | 0.65 | Ambiguous | 0.2 | 1.04 | Ambiguous | 0.85 | Ambiguous | 0.62 | Ambiguous | 0.725 | Likely Pathogenic | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.23 | Pathogenic | 0.15 | Tolerated | 0.1890 | 0.1679 | 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 | 0.86 | Ambiguous | 0.2 | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.88 | Ambiguous | 0.557 | Likely Pathogenic | -3.52 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.10 | Tolerated | 0.2379 | 0.4370 | 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 | 0.42 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.29 | Likely Benign | 0.62 | Ambiguous | 0.639 | Likely Pathogenic | -3.61 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.32 | Pathogenic | 0.09 | Tolerated | 0.1336 | 0.5263 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.1801G>A | A601T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601T 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 are FATHMM and AlphaMissense‑Optimized, whereas the remaining pathogenic‑predicting tools—SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently flag the variant as deleterious. Two tools, FoldX and premPS, return uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, 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 | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -10.635 | Likely Pathogenic | 0.662 | Likely Pathogenic | Likely Benign | 1.55 | Ambiguous | 0.1 | 2.66 | Destabilizing | 2.11 | Destabilizing | 0.76 | Ambiguous | 0.642 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.57 | Benign | 0.00 | Affected | 0.1564 | 0.5554 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1801G>C | A601P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all report pathogenicity. 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 | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -14.584 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 4.90 | Destabilizing | 0.6 | 8.84 | Destabilizing | 6.87 | Destabilizing | 0.87 | Ambiguous | 0.713 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2176 | 0.4328 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1801G>T | A601S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601S 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 FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, and premPS—return uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta outputs, also yields an uncertain result. Overall, more tools (six) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -11.248 | Likely Pathogenic | 0.136 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.21 | Ambiguous | 0.79 | Ambiguous | 0.541 | Likely Pathogenic | -2.99 | Deleterious | 0.983 | Probably Damaging | 0.993 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2732 | 0.4730 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1802C>A | A601E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. 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 assessments reinforce this consensus: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; 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, 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 | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | Conflicting | 2 | -16.752 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 6.68 | Destabilizing | 0.8 | 5.76 | Destabilizing | 6.22 | Destabilizing | 1.24 | Destabilizing | 0.588 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1346 | 0.1444 | 0 | -1 | -5.3 | 58.04 | 240.0 | -82.3 | 0.0 | 0.0 | 0.7 | 0.1 | X | X | X | Potentially Pathogenic | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, the carboxylate group of Glu601 faces the inter-helix space and is forced to shift slightly away from the hydrophobic niche. Additionally, in two of the simulations, Glu601 forms a salt bridge with Arg499, causing the otherwise stable salt bridge between Arg499 and Glu496 at the outer surface of an α helix (res. Leu489-Glu519) to break due to the residue swap.These effects suggest that the protein folding process could be seriously affected. Moreover, due to its location at the GAP-Ras interface, it could also impact the complex formation with the GTPase. | ||||||||||||||
| c.1802C>G | A601G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601G missense variant is listed in gnomAD (ID 6‑33440854‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized; those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The high‑accuracy consensus methods give a pathogenic verdict: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also pathogenic. AlphaMissense‑Default and premPS are uncertain, and no evidence is available from other folding‑stability tools. Overall, the preponderance of evidence points to a pathogenic impact for A601G, 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 | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | 6-33440854-C-G | 1 | 6.19e-7 | -11.772 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.03 | Destabilizing | 0.0 | 2.31 | Destabilizing | 2.17 | Destabilizing | 0.94 | Ambiguous | 0.511 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2337 | 0.4370 | 0 | 1 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1802C>T | A601V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601V is listed in ClinVar (ID 968190.0) with an uncertain clinical significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Four tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | Uncertain | 1 | -10.447 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 1.64 | Ambiguous | 0.1 | 0.35 | Likely Benign | 1.00 | Ambiguous | 0.81 | Ambiguous | 0.535 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.74 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1338 | 0.5263 | 0 | 0 | 2.4 | 28.05 | 228.5 | -45.5 | 0.0 | 0.0 | 0.4 | 0.5 | X | Potentially Benign | The methyl side chain of Ala601, located on an α helix (res. Glu582-Met603), packs hydrophobically against other hydrophobic residues in the inter-helix space (e.g., Phe597, Leu598, Leu506, Phe608).In the variant simulations, Val601, which has similar size and physicochemical properties to alanine, resides in the inter-helix hydrophobic space in a similar manner to Ala601 in the WT, causing no apparent negative effect on the protein structure. However, 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.2056G>A | G686S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G686S is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Foldetta, SIFT, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is also “Likely Pathogenic.” Uncertain predictions from Rosetta and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (a combined FoldX‑MD and Rosetta stability method) as benign. Overall, the majority of evidence points to a pathogenic effect, 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 | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -10.884 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.3 | 0.50 | Ambiguous | 0.40 | Likely Benign | 0.69 | Ambiguous | 0.537 | Likely Pathogenic | -5.29 | Deleterious | 0.998 | Probably Damaging | 0.929 | Probably Damaging | 3.46 | Benign | 0.06 | Tolerated | 0.2558 | 0.4355 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.2056G>C | G686R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, whereas the remaining tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) all predict a pathogenic impact; FoldX is listed as uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to 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 | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -14.801 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.79 | Ambiguous | 0.3 | 0.15 | Likely Benign | 0.47 | Likely Benign | 1.10 | Destabilizing | 0.503 | Likely Pathogenic | -7.21 | Deleterious | 0.974 | Probably Damaging | 0.449 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 0.0951 | 0.3580 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.2056G>T | G686C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, FATHMM, and the protein‑folding stability method Foldetta; pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, with the SGM‑Consensus score labeling the variant as Likely Pathogenic. High‑accuracy assessments further 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 evidence points toward 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 | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -12.790 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.2 | 0.41 | Likely Benign | 0.33 | Likely Benign | 0.93 | Ambiguous | 0.553 | Likely Pathogenic | -8.14 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.31 | Benign | 0.02 | Affected | 0.1209 | 0.3246 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.2057G>A | G686D 2D AIThe SynGAP1 missense variant G686D 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. 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 for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -14.109 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 1.7 | 2.61 | Destabilizing | 2.31 | Destabilizing | 1.05 | Destabilizing | 0.563 | Likely Pathogenic | -6.28 | Deleterious | 1.000 | Probably Damaging | 0.967 | Probably Damaging | 3.40 | Benign | 0.00 | Affected | 0.1720 | 0.2196 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.2057G>C | G686A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy methods give a pathogenic verdict from AlphaMissense‑Optimized and a Likely Pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while Foldetta predicts benign stability. Overall, the majority of evidence points to a pathogenic 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 | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -9.975 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.39 | Likely Benign | 0.2 | -0.46 | Likely Benign | -0.43 | Likely Benign | 0.58 | Ambiguous | 0.321 | Likely Benign | -5.19 | Deleterious | 0.993 | Probably Damaging | 0.732 | Possibly Damaging | 3.37 | Benign | 0.13 | Tolerated | 0.3744 | 0.4131 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2057G>T | G686V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686V has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on benign impact 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 score (Likely Pathogenic) indicate a pathogenic effect. Uncertain results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for G686V, 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 | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -13.751 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.89 | Ambiguous | 0.5 | 0.21 | Likely Benign | 0.55 | Ambiguous | 0.74 | Ambiguous | 0.570 | Likely Pathogenic | -8.08 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.1059 | 0.3646 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1843C>A | P615T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615T is not reported in ClinVar and is absent from gnomAD. Among the evaluated in‑silico predictors, SIFT is the sole tool that predicts a benign effect, whereas the remaining majority—including REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. Predictions from Rosetta, Foldetta, and premPS are uncertain and do not provide definitive evidence. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates it is likely pathogenic, while Foldetta’s stability analysis remains inconclusive. Based on the preponderance of pathogenic predictions and the lack of benign consensus, 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 | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -13.764 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.02 | Destabilizing | 0.3 | 0.95 | Ambiguous | 1.99 | Ambiguous | 0.75 | Ambiguous | 0.823 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.26 | Pathogenic | 0.06 | Tolerated | 0.1602 | 0.3806 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.1843C>G | P615A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P615A variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include SIFT and Rosetta, whereas the majority of predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) all suggest a pathogenic impact. Uncertain results are reported by FoldX, Foldetta, and premPS. 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’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P615A, 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 | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -12.156 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 1.73 | Ambiguous | 0.3 | 0.35 | Likely Benign | 1.04 | Ambiguous | 0.85 | Ambiguous | 0.693 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 0.3169 | 0.3214 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1843C>T | P615S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615S is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a pathogenic effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM Consensus also indicates a likely pathogenic outcome. No tools predict a benign 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, while Foldetta’s stability prediction is uncertain and therefore not taken as evidence. Overall, the preponderance of evidence points to the variant being most likely pathogenic, with no contradiction to the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -12.566 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.87 | Ambiguous | 0.98 | Ambiguous | 0.780 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.19 | Pathogenic | 0.04 | Affected | 0.3191 | 0.3310 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1844C>A | P615Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change P615Q is not listed in ClinVar and has no allele record in gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly classify the variant as pathogenic: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only Rosetta and the combined Foldetta stability assessment are inconclusive. Grouping the predictions, the benign category contains no tools, while the pathogenic category includes all the above. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic, and Foldetta remains uncertain. 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 | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -13.247 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.72 | Ambiguous | 1.33 | Destabilizing | 0.742 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.28 | Pathogenic | 0.01 | Affected | 0.1395 | 0.3445 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||
| c.1844C>G | P615R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. 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. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -15.628 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.62 | Destabilizing | 0.5 | 2.69 | Destabilizing | 2.66 | Destabilizing | 1.14 | Destabilizing | 0.871 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.1463 | 0.2603 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1844C>T | P615L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615L 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 premPS and Rosetta, whereas the remaining tools—REVEL, FoldX, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, PROVEAN, and the SGM Consensus—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) also predicts pathogenicity, and Foldetta yields an uncertain result. Taken together, the overwhelming majority of computational evidence indicates that P615L is likely pathogenic, 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 | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -11.884 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.03 | Destabilizing | 0.4 | -0.01 | Likely Benign | 1.01 | Ambiguous | 0.50 | Likely Benign | 0.699 | Likely Pathogenic | -9.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.13 | Pathogenic | 0.04 | Affected | 0.1949 | 0.4692 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.1972G>A | G658S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G658S is reported in gnomAD (variant ID 6-33441231‑G‑A) but has no entry in ClinVar. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity; the only inconclusive result comes from Rosetta, which is treated as unavailable. High‑accuracy assessments reinforce this view: 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, also predicts benign. Consequently, 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 | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | 6-33441231-G-A | 8 | 4.96e-6 | -3.445 | Likely Benign | 0.077 | Likely Benign | Likely Benign | -0.12 | Likely Benign | 0.0 | -0.50 | Ambiguous | -0.31 | Likely Benign | -0.11 | Likely Benign | 0.070 | Likely Benign | -0.97 | Neutral | 0.209 | Benign | 0.087 | Benign | 3.58 | Benign | 0.43 | Tolerated | 3.39 | 24 | 0.2783 | 0.3576 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||
| c.1972G>C | G658R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G658R is not reported in ClinVar and has no entries in 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) and AlphaMissense‑Default. Four tools (FoldX, Foldetta, premPS, ESM1b) return uncertain results. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is uncertain. Because the majority of conventional predictors lean benign and no ClinVar evidence contradicts this, the variant is most likely benign, though the conflicting high‑accuracy predictions leave some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | -7.725 | In-Between | 0.618 | Likely Pathogenic | Likely Benign | -1.17 | Ambiguous | 0.1 | -0.46 | Likely Benign | -0.82 | Ambiguous | 0.64 | Ambiguous | 0.120 | Likely Benign | -3.11 | Deleterious | 0.955 | Possibly Damaging | 0.591 | Possibly Damaging | 3.40 | Benign | 0.19 | Tolerated | 0.1157 | 0.3888 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1972G>T | G658C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G658C 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. One tool, ESM1b, yields an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign (2 benign vs. 1 pathogenic, 1 uncertain), and Foldetta predicts a benign impact on protein stability. Overall, the majority of evidence points to a benign effect. 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 | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | -7.577 | In-Between | 0.170 | Likely Benign | Likely Benign | 0.05 | Likely Benign | 0.0 | 0.04 | Likely Benign | 0.05 | Likely Benign | 0.46 | Likely Benign | 0.146 | Likely Benign | -3.49 | Deleterious | 0.989 | Probably Damaging | 0.544 | Possibly Damaging | 3.37 | Benign | 0.04 | Affected | 0.1509 | 0.3141 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1973G>A | G658D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G658D is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6-33441232‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome, while Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta, which integrates FoldX‑MD and Rosetta, is also inconclusive. Overall, the preponderance of evidence points to 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. | GAP | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | Uncertain | 1 | 6-33441232-G-A | 3 | 1.86e-6 | -7.786 | In-Between | 0.442 | Ambiguous | Likely Benign | -0.40 | Likely Benign | 0.1 | -0.59 | Ambiguous | -0.50 | Ambiguous | 0.46 | Likely Benign | 0.144 | Likely Benign | -2.64 | Deleterious | 0.008 | Benign | 0.005 | Benign | 3.53 | Benign | 0.38 | Tolerated | 3.39 | 24 | 0.2106 | 0.2333 | 1 | -1 | -3.1 | 58.04 | 219.8 | -84.3 | 0.0 | 0.0 | 0.2 | 0.1 | X | Potentially Pathogenic | Gly658, located on the outer surface of an α helix (res. Ser641-Glu666), weakens the helix integrity at that spot, which is necessary for the kink in the middle of the long helix. In the variant simulations, the carboxylic acid side chain of Asp658 is on the surface of the α helix and is not involved in any interactions. However, aspartate is not as effective a breaker of the secondary structure element as glycine, which may lead to misfolding. | ||||||||||||||
| c.1973G>C | G658A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G658A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, and the SGM‑Consensus score indicates a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized returns a benign prediction, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign result, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain outcome. Taken together, the evidence overwhelmingly supports a benign impact for G658A, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | -4.303 | Likely Benign | 0.083 | Likely Benign | Likely Benign | -0.34 | Likely Benign | 0.0 | -0.75 | Ambiguous | -0.55 | Ambiguous | -0.18 | Likely Benign | 0.072 | Likely Benign | -0.93 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.47 | Benign | 0.36 | Tolerated | 0.3937 | 0.3352 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1973G>T | G658V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G658V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv; Rosetta’s output is uncertain and therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) as Benign. Taken together, the majority of reliable predictors indicate a benign impact. Thus, 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 | GAP | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | -6.815 | Likely Benign | 0.166 | Likely Benign | Likely Benign | -0.07 | Likely Benign | 0.0 | -0.71 | Ambiguous | -0.39 | Likely Benign | 0.34 | Likely Benign | 0.117 | Likely Benign | -3.23 | Deleterious | 0.841 | Possibly Damaging | 0.264 | Benign | 3.38 | Benign | 0.13 | Tolerated | 0.1337 | 0.3330 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1924A>C | K642Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 K642Q is not reported in ClinVar and has no allele in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and polyPhen‑2 HumVar; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows 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. No other high‑confidence predictions are available. Overall, the balance of evidence leans toward a benign effect, with the single high‑accuracy pathogenic signal from SGM‑Consensus not contradicting the lack of ClinVar annotation. Thus, the variant is most likely benign, and this assessment does not conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -12.186 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.0 | 0.17 | Likely Benign | 0.13 | Likely Benign | 0.42 | Likely Benign | 0.380 | Likely Benign | -3.88 | Deleterious | 0.576 | Possibly Damaging | 0.383 | Benign | 2.87 | Benign | 0.02 | Affected | 0.4477 | 0.1253 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1924A>G | K642E 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K642E is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized). High‑accuracy methods give a mixed signal: 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 stability. No prediction is inconclusive. Overall, the majority of tools lean toward pathogenicity, 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. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.287 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.1 | -0.13 | Likely Benign | 0.07 | Likely Benign | 0.40 | Likely Benign | 0.404 | Likely Benign | -3.92 | Deleterious | 0.116 | Benign | 0.011 | Benign | 2.96 | Benign | 0.03 | Affected | 0.3865 | 0.1013 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1925A>C | K642T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642T is listed in ClinVar (ID 437411.0) as Pathogenic and is not reported in gnomAD. Functional prediction tools split in a 7‑to‑5 ratio: pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while benign calls come from REVEL, Rosetta, Foldetta, premPS, and FATHMM; FoldX and AlphaMissense‑Optimized are uncertain. 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 stability outputs) as Benign. Overall, the majority of evidence points to a pathogenic effect, 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 | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | Likely Pathogenic | 1 | -12.823 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.53 | Ambiguous | 0.1 | 0.30 | Likely Benign | 0.42 | Likely Benign | 0.28 | Likely Benign | 0.484 | Likely Benign | -5.88 | Deleterious | 0.872 | Possibly Damaging | 0.839 | Possibly Damaging | 2.86 | Benign | 0.00 | Affected | 3.37 | 31 | 0.1899 | 0.3270 | 0 | -1 | 3.2 | -27.07 | 213.5 | -8.7 | -0.3 | 0.4 | 0.3 | 0.2 | X | Uncertain | The amino side chain of Lys642, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the shorter side chain of Thr642 forms hydrogen bonds with Glu643 and Thr640 on the same α helix.Regardless, Lys642 is positioned directly at the GAP-Ras interface, and in the SynGAP-Ras WT simulations, its amino side chain forms salt bridges with the carboxylate groups of Ras residues Asp33 and Asp38. The shorter Thr642 is more likely to prefer hydrogen bonding with Glu643 and Thr640 on the same α helix, even in the Ras complex. Thus, the effect of the residue swap on the complex formation with the GTPase cannot be explored using solvent-only simulations. | ||||||||||||||||
| c.1925A>G | K642R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642R is not reported in ClinVar and has no entries in gnomAD. Prediction tools that assess pathogenicity largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign. In contrast, PROVEAN, SIFT, and ESM1b predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, Foldetta is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the balance of evidence favors a benign classification, 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 | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -10.562 | Likely Pathogenic | 0.192 | Likely Benign | Likely Benign | -0.13 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.13 | Likely Benign | 0.04 | Likely Benign | 0.319 | Likely Benign | -2.79 | Deleterious | 0.001 | Benign | 0.001 | Benign | 2.91 | Benign | 0.02 | Affected | 0.4962 | 0.1262 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.1925A>T | K642M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess the variant’s effect fall into two broad groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give uncertain results: Rosetta and Foldetta. 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 as follows: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus also predicts pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence from multiple independent predictors indicates that K642M 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 | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -13.557 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.43 | Likely Benign | 0.1 | 0.62 | Ambiguous | 0.53 | Ambiguous | 0.21 | Likely Benign | 0.510 | Likely Pathogenic | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.941 | Probably Damaging | 2.81 | Benign | 0.00 | Affected | 0.1256 | 0.3589 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1926G>C | K642N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K642N 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, Foldetta, premPS, FATHMM, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. With two of the three high‑accuracy tools supporting pathogenicity and an overall balance 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 | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.423 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.273 | Likely Benign | -4.88 | Deleterious | 0.958 | Probably Damaging | 0.392 | Benign | 2.88 | Benign | 0.00 | Affected | 0.3553 | 0.1590 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1926G>T | K642N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K642N 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, and FATHMM, while those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar (benign). 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, seven tools favor pathogenicity versus six favoring benign, and the high‑accuracy predictions are mixed. Thus, the variant is most likely pathogenic based on the preponderance of 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 | 0.061840 | Structured | 0.181468 | Uncertain | 0.806 | 0.289 | 0.000 | -11.423 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.274 | Likely Benign | -4.88 | Deleterious | 0.958 | Probably Damaging | 0.392 | Benign | 2.88 | Benign | 0.00 | Affected | 0.3553 | 0.1590 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1840T>A | Y614N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y614N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas the majority of other in silico predictors (Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; FoldX is inconclusive and is treated as unavailable. 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) also predicts pathogenic. Taken together, the preponderance of evidence points to a pathogenic effect for Y614N, 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 | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -13.004 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.32 | Ambiguous | 0.5 | 3.16 | Destabilizing | 2.24 | Destabilizing | 1.58 | Destabilizing | 0.471 | Likely Benign | -8.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.42 | Benign | 0.06 | Tolerated | 0.1944 | 0.0573 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1840T>C | Y614H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y614H 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, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and Rosetta. Tools with uncertain or inconclusive results (FoldX, Foldetta, premPS) are not considered evidence for either side. 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, remains uncertain. Overall, the preponderance of evidence indicates that 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 | GAP | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -9.678 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.5 | 2.38 | Destabilizing | 1.78 | Ambiguous | 0.91 | Ambiguous | 0.397 | Likely Benign | -4.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.58 | Benign | 0.27 | Tolerated | 0.1948 | 0.0373 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1840T>G | Y614D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y614D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM predicts it to be benign, 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) all classify it as pathogenic. High‑accuracy methods 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 pathogenic. No prediction or 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, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -15.073 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.14 | Destabilizing | 0.6 | 4.16 | Destabilizing | 3.15 | Destabilizing | 1.69 | Destabilizing | 0.597 | Likely Pathogenic | -9.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.4013 | 0.0573 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1841A>C | Y614S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y614S is not reported in ClinVar and is present in gnomAD (ID 6‑33440893‑A‑C). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas the majority of algorithms—AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), premPS, Rosetta, Foldetta, and the SGM Consensus—indicate pathogenicity; FoldX remains uncertain. High‑accuracy assessments reinforce the pathogenic signal: 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) predicts a destabilizing, pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification, and 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 Pathogenic | GAP | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | 6-33440893-A-C | 1 | 6.20e-7 | -12.709 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.74 | Ambiguous | 0.4 | 3.25 | Destabilizing | 2.50 | Destabilizing | 2.05 | Destabilizing | 0.482 | Likely Benign | -8.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 3.37 | 35 | 0.4155 | 0.1220 | -2 | -3 | 0.5 | -76.10 | ||||||||||||||||||||||||
| c.1841A>G | Y614C 2D AIThe SynGAP1 missense variant Y614C 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 outputs, also predicts pathogenicity. 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 | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -11.716 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.56 | Ambiguous | 0.7 | 3.21 | Destabilizing | 2.39 | Destabilizing | 1.76 | Destabilizing | 0.539 | Likely Pathogenic | -8.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.41 | Benign | 0.02 | Affected | 0.3081 | 0.1679 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1841A>T | Y614F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y614F 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or unavailable results come from Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is unavailable. Overall, the majority of reliable predictors indicate 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 | 0.314870 | Structured | 0.182134 | Uncertain | 0.852 | 0.254 | 0.000 | -5.584 | Likely Benign | 0.630 | Likely Pathogenic | Likely Benign | 0.09 | Likely Benign | 0.2 | 0.98 | Ambiguous | 0.54 | Ambiguous | 0.78 | Ambiguous | 0.364 | Likely Benign | -3.75 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 0.1909 | 0.2762 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1804A>C | I602L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I602L 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, PROVEAN, and AlphaMissense‑Optimized, whereas a majority of tools predict pathogenicity: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Three tools (Rosetta, 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 balance of evidence leans toward pathogenicity, with no conflict with the ClinVar status because the variant is not yet classified in that database. 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 | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -9.660 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | -0.15 | Likely Benign | 0.1 | 1.12 | Ambiguous | 0.49 | Likely Benign | 0.91 | Ambiguous | 0.631 | Likely Pathogenic | -1.99 | Neutral | 0.645 | Possibly Damaging | 0.718 | Possibly Damaging | -1.54 | Pathogenic | 0.04 | Affected | 0.1044 | 0.3199 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1804A>G | I602V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I602V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the change as benign include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, SIFT, and FATHMM. Uncertain or inconclusive results come from FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by any ClinVar annotation, 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 | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -6.317 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 0.0 | 0.78 | Ambiguous | 1.01 | Ambiguous | 1.01 | Destabilizing | 0.309 | Likely Benign | -0.84 | Neutral | 0.528 | Possibly Damaging | 0.179 | Benign | -1.89 | Pathogenic | 0.03 | Affected | 0.1173 | 0.3326 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1804A>T | I602F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I602F missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign outcome. Predictions that are uncertain or inconclusive are 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 as Uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Therefore, 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 | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -13.974 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 1.1 | -0.61 | Ambiguous | 0.93 | Ambiguous | 0.87 | Ambiguous | 0.822 | Likely Pathogenic | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.937 | Probably Damaging | -1.82 | Pathogenic | 0.00 | Affected | 0.0708 | 0.2343 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1805T>A | I602N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I602N 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 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 damaging impact. Therefore, 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 | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -16.033 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.94 | Destabilizing | 0.2 | 3.34 | Destabilizing | 3.14 | Destabilizing | 2.31 | Destabilizing | 0.880 | Likely Pathogenic | -6.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.01 | Pathogenic | 0.00 | Affected | 0.0718 | 0.0700 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1805T>C | I602T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I602T 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 the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as pathogenic or likely pathogenic. No tool reports a benign outcome. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Consequently, the variant is most likely pathogenic according to the available computational evidence, 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 Pathogenic | GAP | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -12.238 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 2.39 | Destabilizing | 0.1 | 2.14 | Destabilizing | 2.27 | Destabilizing | 1.94 | Destabilizing | 0.931 | Likely Pathogenic | -4.82 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | -2.00 | Pathogenic | 0.00 | Affected | 0.0890 | 0.0989 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1805T>G | I602S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I602S 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 corroborate this: 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 conflicting benign evidence is available. Therefore, based on the consensus of all available predictions, the variant is most likely pathogenic, 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 | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -15.558 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 3.50 | Destabilizing | 0.1 | 3.79 | Destabilizing | 3.65 | Destabilizing | 2.04 | Destabilizing | 0.935 | Likely Pathogenic | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.01 | Pathogenic | 0.00 | Affected | 0.2213 | 0.1087 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.1806T>G | I602M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I602M 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 FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. In contrast, the majority of tools predict it to be pathogenic: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show a split: AlphaMissense‑Optimized and Foldetta both predict benign, whereas the SGM‑Consensus predicts pathogenic. Based on the overall distribution of 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 | 0.010221 | Structured | 0.186541 | Uncertain | 0.963 | 0.171 | 0.000 | -10.839 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | 0.03 | Likely Benign | 0.1 | 0.48 | Likely Benign | 0.26 | Likely Benign | 1.10 | Destabilizing | 0.675 | Likely Pathogenic | -2.91 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.97 | Pathogenic | 0.00 | Affected | 0.0801 | 0.2321 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.2059C>G | R687G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R687G missense variant 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 (SGM‑Consensus, 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: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta indicates a destabilizing, pathogenic effect. AlphaMissense‑Optimized is uncertain and therefore treated as unavailable. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, 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 | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | -12.900 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 2.94 | Destabilizing | 0.3 | 2.53 | Destabilizing | 2.74 | Destabilizing | 1.27 | Destabilizing | 0.360 | Likely Benign | -6.26 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 0.2508 | 0.2119 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.2060G>A | R687Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R687Q is annotated in ClinVar as benign (ClinVar ID 2693600.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, SGM‑Consensus indicating pathogenicity, and Foldetta (integrating FoldX‑MD and Rosetta outputs) classifying it as benign. With three high‑accuracy tools giving benign or uncertain results and only one (SGM‑Consensus) suggesting pathogenicity, the overall evidence leans toward a benign effect. This prediction aligns with the ClinVar benign classification, indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | Likely Benign | 1 | -10.002 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | 0.92 | Ambiguous | 0.1 | -0.37 | Likely Benign | 0.28 | Likely Benign | 1.55 | Destabilizing | 0.401 | Likely Benign | -3.37 | Deleterious | 1.000 | Probably Damaging | 0.844 | Possibly Damaging | 3.91 | Benign | 0.03 | Affected | 3.42 | 17 | 0.2143 | 0.1952 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||
| c.2060G>C | R687P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R687P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining eleven tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; 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. With the overwhelming majority of evidence pointing to a damaging effect and no conflicting ClinVar annotation, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | -15.697 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.3 | 6.63 | Destabilizing | 4.47 | Destabilizing | 0.89 | Ambiguous | 0.553 | Likely Pathogenic | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.87 | Benign | 0.01 | Affected | 0.1811 | 0.3159 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.2060G>T | R687L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R687L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign include REVEL, SIFT, ESM1b, and FATHMM, while those that agree on pathogenic are AlphaMissense‑Default, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The remaining tools—AlphaMissense‑Optimized, FoldX, Foldetta, and premPS—return uncertain or inconclusive results. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Consequently, the evidence does not strongly support either benign or pathogenic classification. The variant is therefore most likely inconclusive, 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 | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | -6.925 | Likely Benign | 0.901 | Likely Pathogenic | Ambiguous | 1.43 | Ambiguous | 0.3 | 0.05 | Likely Benign | 0.74 | Ambiguous | 0.83 | Ambiguous | 0.448 | Likely Benign | -5.76 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 3.90 | Benign | 0.10 | Tolerated | 0.1252 | 0.3376 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||
| 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 | 1.54 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.33 | Ambiguous | 0.92 | Ambiguous | 0.586 | Likely Pathogenic | -3.03 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.28 | Pathogenic | 0.17 | Tolerated | 0.2707 | 0.1849 | 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 | 2.07 | Destabilizing | 0.3 | 1.87 | Ambiguous | 1.97 | Ambiguous | 1.29 | Destabilizing | 0.674 | Likely Pathogenic | -4.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.34 | Pathogenic | 0.04 | Affected | 0.2920 | 0.1998 | -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 | 1.00 | Ambiguous | 0.0 | 1.13 | Ambiguous | 1.07 | Ambiguous | 0.72 | Ambiguous | 0.691 | Likely Pathogenic | -5.49 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3055 | 0.1546 | -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 | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | 0.730 | Likely Pathogenic | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2343 | 0.0746 | 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 | 3.69 | Destabilizing | 0.1 | 8.87 | Destabilizing | 6.28 | Destabilizing | 1.02 | Destabilizing | 0.823 | Likely Pathogenic | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.03 | Affected | 0.2223 | 0.2725 | 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 | 0.71 | Ambiguous | 0.2 | -0.33 | Likely Benign | 0.19 | Likely Benign | 0.52 | Ambiguous | 0.686 | Likely Pathogenic | -4.53 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.26 | Pathogenic | 0.11 | Tolerated | 0.1666 | 0.2857 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1816A>C | S606R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain outcomes are Foldetta, premPS, and Rosetta. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Overall, the majority of high‑confidence predictions and the consensus vote indicate a pathogenic effect. Because ClinVar contains no entry for this variant, there is no contradiction between the computational evidence and clinical annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.252 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1816A>G | S606G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S606G is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized, 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 classifying the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result and is treated as unavailable. Overall, the majority 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 | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.281 | Likely Pathogenic | 0.603 | Likely Pathogenic | Likely Benign | 0.43 | Likely Benign | 0.1 | 1.42 | Ambiguous | 0.93 | Ambiguous | 0.84 | Ambiguous | 0.229 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 3.35 | Benign | 0.04 | Affected | 0.2286 | 0.3279 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.1816A>T | S606C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606C 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are 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 the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign, and the SGM‑Consensus as Likely Pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overall distribution of predictions, the variant is most likely benign, although the SGM‑Consensus suggests pathogenicity; this does not contradict any ClinVar status because the variant is not yet classified in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -11.122 | Likely Pathogenic | 0.774 | Likely Pathogenic | Likely Benign | -0.34 | Likely Benign | 0.0 | -0.31 | Likely Benign | -0.33 | Likely Benign | 0.49 | Likely Benign | 0.348 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.31 | Benign | 0.00 | Affected | 0.0986 | 0.4580 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.1817G>A | S606N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S606N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, Rosetta, SIFT, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Because the majority of individual predictors lean toward pathogenic and the SGM‑Consensus, a high‑confidence consensus, also indicates pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict 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 | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -11.352 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.11 | Likely Benign | 0.1 | 0.20 | Likely Benign | 0.16 | Likely Benign | 0.76 | Ambiguous | 0.136 | Likely Benign | -2.99 | Deleterious | 0.920 | Possibly Damaging | 0.955 | Probably Damaging | 3.37 | Benign | 0.10 | Tolerated | 0.1137 | 0.3218 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.1817G>C | S606T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606T 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, FATHMM, and AlphaMissense‑Optimized, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results come from Rosetta, premPS, and AlphaMissense‑Default. 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. Overall, the majority of tools predict pathogenicity, and the SGM Consensus supports this view, while the high‑accuracy methods give mixed results. Thus, the variant is most likely pathogenic based on 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. | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -11.052 | Likely Pathogenic | 0.554 | Ambiguous | Likely Benign | 0.06 | Likely Benign | 0.1 | -0.91 | Ambiguous | -0.43 | Likely Benign | 0.57 | Ambiguous | 0.203 | Likely Benign | -2.99 | Deleterious | 0.826 | Possibly Damaging | 0.933 | Probably Damaging | 3.34 | Benign | 0.03 | Affected | 0.1260 | 0.4513 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1817G>T | S606I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, Rosetta, Foldetta, premPS, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX is uncertain. 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 benign. Overall, the majority of evidence points toward a pathogenic impact for S606I. This conclusion is not contradicted by 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 | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -14.552 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | -0.60 | Ambiguous | 0.1 | -0.08 | Likely Benign | -0.34 | Likely Benign | 0.41 | Likely Benign | 0.288 | Likely Benign | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.0891 | 0.4162 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.1818T>A | S606R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a separate group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with uncertain outcomes are Foldetta, premPS, and Rosetta. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains inconclusive. Overall, the majority of high‑confidence predictions and the consensus vote indicate a pathogenic effect. Because ClinVar contains no entry for this variant, there is no contradiction between the computational evidence and clinical annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.246 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1818T>G | S606R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606R is not reported in ClinVar or gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, SIFT, and FATHMM, whereas a majority predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. High‑accuracy methods confirm the pathogenic trend: AlphaMissense‑Optimized is pathogenic, SGM Consensus is Likely Pathogenic, and Foldetta remains uncertain. Overall, the evidence points to the variant being most likely pathogenic, 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 | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -12.900 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.4 | 1.80 | Ambiguous | 0.98 | Ambiguous | 0.82 | Ambiguous | 0.246 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.38 | Benign | 0.08 | Tolerated | 0.0819 | 0.2750 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1810T>A | S604T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive (FoldX, Rosetta, AlphaMissense‑Optimized) are treated as unavailable. 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 (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall pattern of predictions, the variant is most likely pathogenic, 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 | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -9.674 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.64 | Ambiguous | 0.1 | -0.58 | Ambiguous | 0.03 | Likely Benign | -0.16 | Likely Benign | 0.337 | Likely Benign | -2.99 | Deleterious | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | 3.19 | Benign | 0.08 | Tolerated | 0.1687 | 0.4919 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1810T>C | S604P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also labels the variant as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence supports a pathogenic classification for S604P, 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 | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.953 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.76 | Destabilizing | 0.3 | 8.40 | Destabilizing | 6.08 | Destabilizing | 0.04 | Likely Benign | 0.512 | Likely Pathogenic | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 3.10 | Benign | 0.01 | Affected | 0.2524 | 0.4829 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1810T>G | S604A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604A has no ClinVar record and is not reported in gnomAD. 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 SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain and does not contribute to a consensus. 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. With two of the three high‑accuracy tools indicating benign and no ClinVar evidence to contradict, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.017 | Likely Pathogenic | 0.608 | Likely Pathogenic | Likely Benign | 0.02 | Likely Benign | 0.1 | -0.60 | Ambiguous | -0.29 | Likely Benign | 0.11 | Likely Benign | 0.378 | Likely Benign | -2.99 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | 3.25 | Benign | 0.08 | Tolerated | 0.5198 | 0.3530 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.1811C>G | S604W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant S604W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are provided by Rosetta, premPS, and FATHMM. Stability‑based methods give mixed results: FoldX is uncertain, while Foldetta is also uncertain. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenic. Foldetta remains inconclusive. Overall, the consensus of the majority of tools indicates a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -19.117 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -1.23 | Ambiguous | 0.1 | -2.05 | Stabilizing | -1.64 | Ambiguous | -0.19 | Likely Benign | 0.645 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.07 | Benign | 0.00 | Affected | 0.0818 | 0.4602 | -2 | -3 | -0.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1811C>T | S604L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604L is listed in ClinVar with an “Uncertain” status (ClinVar ID 1055027.0) and is present in gnomAD (ID 6‑33440863‑C‑T). Prediction tools that agree on a benign effect are premPS and FATHMM. Tools that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, 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, 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 | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | Uncertain | 1 | 6-33440863-C-T | 6 | 3.72e-6 | -14.683 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | -0.94 | Ambiguous | 0.1 | -1.24 | Ambiguous | -1.09 | Ambiguous | -0.31 | Likely Benign | 0.639 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1177 | 0.4518 | -3 | -2 | 4.6 | 26.08 | 234.0 | -49.6 | 0.0 | 0.1 | 0.3 | 0.5 | X | X | Potentially Pathogenic | Ser604 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). In the WT simulations, the hydroxyl side chain of Ser604 periodically hydrogen bonds with the backbone carbonyl groups of other α helix residues (e.g., Pro600, Met603). Serine weakens the α helix secondary structure, and thus, Ser604 along with Pro605 breaks the α helix, facilitating the turn in the WT structure.In contrast, in the variant simulations, Leu604 forms a few hydrophobic interactions (e.g., Leu607, Phe608). More importantly, the helix end is more stable than with Ser604 in the WT. The residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end, than what the simulations suggest.Moreover, Ser604 directly hydrogen bonds with Ras residues Ser65 and Ala66 in the WT SynGAP-Ras complex. The hydrophobic leucine cannot maintain these interactions with Ras at the GAP-Ras interface. Thus, the effect of the residue swap on the complex formation with the GTPase cannot be fully explored in the solvent-only simulations. | ||||||||||||
| c.1813C>A | P605T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605T 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, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign outcome. High‑accuracy methods specifically show pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -11.533 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.87 | Destabilizing | 0.4 | 2.14 | Destabilizing | 2.51 | Destabilizing | 0.72 | Ambiguous | 0.801 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 0.1626 | 0.5228 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.1813C>G | P605A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic, while premPS remains uncertain. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, and 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 Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -10.085 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 2.58 | Destabilizing | 0.3 | 2.42 | Destabilizing | 2.50 | Destabilizing | 0.91 | Ambiguous | 0.744 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.75 | Pathogenic | 0.00 | Affected | 0.3432 | 0.4607 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1813C>T | P605S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All evaluated in‑silico predictors classify the change 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: 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. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, which contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | Uncertain | 1 | -10.830 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.40 | Destabilizing | 0.1 | 3.34 | Destabilizing | 3.37 | Destabilizing | 1.00 | Destabilizing | 0.718 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.70 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3397 | 0.4676 | 1 | -1 | 0.8 | -10.04 | 213.8 | -15.4 | -0.3 | 0.2 | 0.2 | 0.1 | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the hydroxyl side chain of Ser605 forms hydrogen bonds with the backbone carbonyl groups of Ala601 and Ile602. Importantly, the helix end is more stable than with Pro605 in the WT. Indeed, proline is a more effective secondary structure breaker compared to serine.Thus, the residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end, than what the simulations suggest. Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | |||||||||||||||
| c.1814C>A | P605H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605H is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include 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 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 (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available predictions are consistent and indicate a deleterious effect. Consequently, the variant is most likely pathogenic, and this assessment 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. | Likely Pathogenic | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -13.846 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 8.80 | Destabilizing | 2.7 | 6.69 | Destabilizing | 7.75 | Destabilizing | 0.87 | Ambiguous | 0.828 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 0.1778 | 0.4142 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.1814C>G | P605R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains inconclusive. Grouping by consensus, the benign category is empty and the pathogenic category contains all available predictions. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta outputs, reports a destabilizing, pathogenic effect. Consequently, 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 | GAP | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | Uncertain | 1 | -13.745 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 8.71 | Destabilizing | 2.5 | 6.46 | Destabilizing | 7.59 | Destabilizing | 0.92 | Ambiguous | 0.845 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.1458 | 0.3131 | 0 | -2 | -2.9 | 59.07 | 281.7 | -118.1 | -0.2 | 0.0 | 0.5 | 0.1 | X | X | X | X | Potentially Pathogenic | Pro605 is located in a short turn between an α helix (res. Glu582-Met603) and a short α helical section (res. Ser606-Phe608). The pyrrolidine side chain of Pro605 packs hydrophobically with nearby hydrophobic residues (e.g., Ile514, Leu623, Leu610) in the inter-helix space. Additionally, proline lacks a free backbone amide group, which breaks the α helix and facilitates the turn in the WT structure.In the variant simulations, the guanidinium side chain of Arg605 is bulkier than proline, and its positively charged guanidinium group faces mostly hydrophobic residues (e.g., Ile514, Leu623, Leu610). As a result, it needs to rotate away from the hydrophobic niche. The residue swap could have a more profound effect on the actual folding process, for example, by preventing the bending at the α helix end.Moreover, due to its location at the GAP-Ras interface, the residue swap could affect the GAP-Ras association. | |||||||||||||
| c.1814C>T | P605L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P605L 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. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic; 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 pathogenic effect. Based on the overwhelming agreement among 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 | 0.023087 | Structured | 0.192737 | Uncertain | 0.929 | 0.231 | 0.000 | -12.114 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.65 | Destabilizing | 1.1 | 2.74 | Destabilizing | 2.70 | Destabilizing | -0.10 | Likely Benign | 0.814 | Likely Pathogenic | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.69 | Pathogenic | 0.00 | Affected | 0.2232 | 0.6158 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.1837G>A | E613K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E613K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Foldetta, and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments give AlphaMissense‑Optimized as pathogenic, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction is inconclusive. Overall, the majority of evidence points to a pathogenic effect, 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 | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -11.892 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.6 | -0.54 | Ambiguous | -0.10 | Likely Benign | -0.08 | Likely Benign | 0.567 | Likely Pathogenic | -3.72 | Deleterious | 0.996 | Probably Damaging | 0.987 | Probably Damaging | -1.15 | Pathogenic | 0.04 | Affected | 0.2979 | 0.5942 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1837G>C | E613Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E613Q 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, and SIFT, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts a likely pathogenic outcome, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Overall, the balance of evidence leans toward pathogenicity, and this assessment 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 | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -9.245 | Likely Pathogenic | 0.887 | Likely Pathogenic | Ambiguous | 0.41 | Likely Benign | 0.4 | -0.84 | Ambiguous | -0.22 | Likely Benign | 0.11 | Likely Benign | 0.495 | Likely Benign | -2.79 | Deleterious | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.28 | Pathogenic | 0.09 | Tolerated | 0.1650 | 0.6181 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1838A>C | E613A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E613A 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 Rosetta, premPS, and Foldetta, whereas 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. 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 stability outputs) as benign. Overall, the preponderance of evidence (10 pathogenic vs. 3 benign predictions) 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 | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -10.841 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.90 | Ambiguous | 0.5 | -0.17 | Likely Benign | 0.37 | Likely Benign | 0.32 | Likely Benign | 0.688 | Likely Pathogenic | -5.57 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.4696 | 0.5929 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1838A>G | E613G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E613G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact. The high‑accuracy methods give the following results: 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, is uncertain. No prediction or stability assessment is missing or inconclusive beyond the uncertain labels. Overall, the preponderance of evidence points to a pathogenic effect for E613G, 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 | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -12.417 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 1.49 | Ambiguous | 0.3 | 1.34 | Ambiguous | 1.42 | Ambiguous | 0.08 | Likely Benign | 0.641 | Likely Pathogenic | -6.56 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.26 | Pathogenic | 0.01 | Affected | 0.3422 | 0.5266 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1838A>T | E613V 2D 3DClick to see structure in 3D Viewer AISynGAP1 E613V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are Foldetta and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. FoldX and Rosetta give uncertain results and are not included in the agreement groups. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Because the majority of evidence points to a deleterious effect, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -12.799 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.5 | -0.76 | Ambiguous | -0.02 | Likely Benign | 0.31 | Likely Benign | 0.767 | Likely Pathogenic | -6.57 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | -1.25 | Pathogenic | 0.03 | Affected | 0.0935 | 0.6565 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1839G>C | E613D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E613D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, and SIFT, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Three tools—FoldX, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic impact for E613D. 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 Pathogenic | GAP | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -8.795 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 0.67 | Ambiguous | 0.3 | 0.48 | Likely Benign | 0.58 | Ambiguous | 0.13 | Likely Benign | 0.474 | Likely Benign | -2.79 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.15 | Tolerated | 0.1998 | 0.4000 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1839G>T | E613D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E613D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, and SIFT, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Three tools—FoldX, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic impact for E613D. 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 Pathogenic | GAP | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -8.795 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 0.67 | Ambiguous | 0.3 | 0.48 | Likely Benign | 0.58 | Ambiguous | 0.13 | Likely Benign | 0.474 | Likely Benign | -2.79 | Deleterious | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.15 | Tolerated | 0.1998 | 0.4000 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1819C>A | L607I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L607I 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, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, while benign calls are made by PROVEAN and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Stability predictions from FoldX, Rosetta, and premPS are inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for L607I. 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 | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -12.061 | Likely Pathogenic | 0.644 | Likely Pathogenic | Likely Benign | 0.63 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.94 | Ambiguous | 0.82 | Ambiguous | 0.727 | Likely Pathogenic | -1.99 | Neutral | 0.992 | Probably Damaging | 0.997 | Probably Damaging | -1.54 | Pathogenic | 0.01 | Affected | 0.1079 | 0.3767 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1819C>G | L607V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L607V is listed in ClinVar with an uncertain significance (ClinVar ID 1450275.0) and is present in gnomAD (ID 6‑33440871‑C‑G). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized reports benign, whereas the SGM‑Consensus, derived from the majority of pathogenic predictions, indicates pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Overall, the preponderance of computational evidence points to a pathogenic effect for L607V, a conclusion that contrasts with the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | Uncertain | 2 | 6-33440871-C-G | 2 | 1.24e-6 | -11.190 | Likely Pathogenic | 0.637 | Likely Pathogenic | Likely Benign | 1.04 | Ambiguous | 0.2 | 1.36 | Ambiguous | 1.20 | Ambiguous | 0.90 | Ambiguous | 0.715 | Likely Pathogenic | -2.99 | Deleterious | 0.985 | Probably Damaging | 0.992 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1634 | 0.3577 | 2 | 1 | 0.4 | -14.03 | 216.3 | 28.1 | 0.1 | 0.0 | 0.9 | 0.2 | X | Potentially Benign | Leu607 is located in a short helical region (res. Ser606-Phe608) within an α-α loop connecting two α helices (res. Glu582-Met603 and res. Glu617-Asn635). In the WT simulations, the iso-butyl side chain of Leu607 does not interact with any other residues, but it could potentially interact directly with Ras due to its location at the GAP domain.In the variant simulations, Val607, which has similar size and physicochemical properties to leucine, does not cause any negative effects on the protein structure. However, due to its location at the GAP-Ras interface, the residue swap could affect the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | |||||||||||||
| c.1819C>T | L607F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607F is catalogued in gnomAD (6‑33440871‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all report pathogenic or likely pathogenic. Only FoldX predicts a benign outcome, while Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show the SGM‑Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L607F, and this conclusion is not contradicted by ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | 6-33440871-C-T | 1 | 6.19e-7 | -13.654 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.1 | 1.20 | Ambiguous | 0.72 | Ambiguous | 0.61 | Ambiguous | 0.758 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.54 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0872 | 0.2816 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||
| c.1820T>A | L607H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on pathogenicity include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign effect. Uncertain predictions come from FoldX, Rosetta, and Foldetta. 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, while Foldetta’s stability analysis is inconclusive. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, 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 | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -14.775 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.1 | 1.88 | Ambiguous | 1.32 | Ambiguous | 1.38 | Destabilizing | 0.906 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.01 | Affected | 0.1199 | 0.0541 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1820T>C | L607P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; the only inconclusive result is FoldX, which is listed as uncertain and therefore does not influence the overall assessment. High‑accuracy methods reinforce this view: 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 predicts pathogenicity. Consequently, the variant is most likely pathogenic based on the available predictions, 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 | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -14.059 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.11 | Ambiguous | 0.7 | 6.93 | Destabilizing | 4.02 | Destabilizing | 1.29 | Destabilizing | 0.922 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.54 | Pathogenic | 0.00 | Affected | 0.3710 | 0.1274 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1820T>G | L607R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607R 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 FoldX, which scores the variant as benign. All other evaluated algorithms—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. Rosetta and Foldetta provide uncertain results and are therefore treated as unavailable evidence. 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,” while Foldetta remains uncertain. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, 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 | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -14.234 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | -0.15 | Likely Benign | 0.1 | 1.48 | Ambiguous | 0.67 | Ambiguous | 1.24 | Destabilizing | 0.920 | Likely Pathogenic | -5.98 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | -1.51 | Pathogenic | 0.01 | Affected | 0.1490 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1822T>A | F608I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenic or likely pathogenic. The only tool with an inconclusive result is FoldX, which is listed as uncertain. No tool predicts a benign outcome. 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 outputs, is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is consistent with the absence of any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -14.939 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.92 | Ambiguous | 0.1 | 2.14 | Destabilizing | 2.03 | Destabilizing | 1.24 | Destabilizing | 0.904 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.62 | Pathogenic | 0.00 | Affected | 0.2115 | 0.2361 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1822T>C | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. FoldX and Foldetta report uncertain stability changes, but these are not considered evidence against pathogenicity. When predictions are grouped, no tool predicts a benign outcome; all available evidence supports a harmful effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from the majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta remains 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 | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.883 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1822T>G | F608V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608V 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, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all of these return a pathogenic or likely pathogenic label. No tool in the dataset predicts a benign outcome. Uncertain results are reported only for Rosetta and Foldetta, which are treated as unavailable evidence. 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 remains uncertain. Taken together, the overwhelming majority of predictions indicate that F608V 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 | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -16.084 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 2.21 | Destabilizing | 0.1 | 1.39 | Ambiguous | 1.80 | Ambiguous | 1.47 | Destabilizing | 0.917 | Likely Pathogenic | -6.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.59 | Pathogenic | 0.01 | Affected | 0.2193 | 0.2199 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1823T>A | F608Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608Y is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a pathogenic effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus all predict pathogenicity, while only Rosetta predicts a benign effect. Tools with uncertain outcomes—FoldX, Foldetta, and AlphaMissense‑Optimized—do not provide decisive evidence. High‑accuracy assessments further support a deleterious impact: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic, whereas AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence indicates that F608Y is most likely pathogenic, 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 Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -13.249 | Likely Pathogenic | 0.812 | Likely Pathogenic | Ambiguous | 0.62 | Ambiguous | 0.1 | 0.41 | Likely Benign | 0.52 | Ambiguous | 1.05 | Destabilizing | 0.747 | Likely Pathogenic | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.976 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 0.1504 | 0.1346 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1823T>C | F608S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608S 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 predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: 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 stability calculations, also predicts pathogenicity. All available predictions are consistent and conclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -15.181 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 3.16 | Destabilizing | 0.2 | 4.00 | Destabilizing | 3.58 | Destabilizing | 1.66 | Destabilizing | 0.917 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.59 | Pathogenic | 0.02 | Affected | 0.4366 | 0.0400 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1823T>G | F608C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608C is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the change as pathogenic; no tool predicts a benign effect. 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 reports a pathogenic effect. Because all evidence points to a deleterious impact and there is no ClinVar entry to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -14.409 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.2 | 3.04 | Destabilizing | 2.75 | Destabilizing | 1.77 | Destabilizing | 0.920 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.67 | Pathogenic | 0.00 | Affected | 0.2738 | 0.1050 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1824T>A | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. FoldX and Foldetta report uncertain stability changes, but these are not considered evidence against pathogenicity. When predictions are grouped, no tool predicts a benign outcome; all available evidence supports a harmful effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from the majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta remains 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 | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.747 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1824T>G | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX‑MD (uncertain), Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FoldX and Foldetta are inconclusive. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it likely pathogenic, and Foldetta reports an uncertain stability change. No tool predicts 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 | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.747 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1807A>C | M603L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 M603L 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 FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized, and the protein‑folding stability method Foldetta. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta 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 benign. Overall, more evidence supports a benign effect (six benign versus five pathogenic predictions, with two uncertain). Thus, 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 | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -7.134 | In-Between | 0.590 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 0.86 | Ambiguous | 0.45 | Likely Benign | -0.18 | Likely Benign | 0.548 | Likely Pathogenic | -2.16 | Neutral | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -0.98 | Pathogenic | 0.52 | Tolerated | 0.1345 | 0.3227 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||
| c.1807A>G | M603V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M603V is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS and SIFT, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. The remaining tools—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—return uncertain or inconclusive results. High‑accuracy assessments reinforce the pathogenic signal: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic, and AlphaMissense‑Optimized is uncertain; Foldetta also remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for M603V. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -10.442 | Likely Pathogenic | 0.800 | Likely Pathogenic | Ambiguous | 1.34 | Ambiguous | 0.2 | 0.62 | Ambiguous | 0.98 | Ambiguous | -0.15 | Likely Benign | 0.668 | Likely Pathogenic | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -0.92 | Pathogenic | 0.09 | Tolerated | 0.2698 | 0.2601 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.1807A>T | M603L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 M603L 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, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Rosetta and ESM1b give uncertain results. 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. Overall, the majority of tools lean toward a benign interpretation, but the SGM Consensus indicates pathogenicity, leaving the variant’s clinical significance uncertain. This assessment does not contradict any ClinVar status, as no ClinVar entry exists for M603L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -7.134 | In-Between | 0.590 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 0.86 | Ambiguous | 0.45 | Likely Benign | -0.18 | Likely Benign | 0.548 | Likely Pathogenic | -2.16 | Neutral | 0.484 | Possibly Damaging | 0.654 | Possibly Damaging | -0.98 | Pathogenic | 0.52 | Tolerated | 0.1345 | 0.3227 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||
| c.1808T>A | M603K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M603K is not reported in ClinVar and has no entries in gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, SGM Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only FoldX reports a benign outcome. High‑accuracy assessments reinforce this trend: 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, is inconclusive. No other tools provide a clear benign signal. Consequently, the variant is most likely pathogenic, 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 | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -15.561 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.17 | Likely Benign | 0.0 | 1.19 | Ambiguous | 0.68 | Ambiguous | 0.67 | Ambiguous | 0.933 | Likely Pathogenic | -5.64 | Deleterious | 0.923 | Possibly Damaging | 0.922 | Probably Damaging | -1.35 | Pathogenic | 0.00 | Affected | 0.1268 | 0.0488 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1808T>C | M603T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M603T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that provide a clear verdict all classify the substitution as pathogenic: 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). No tool in the dataset reports a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus indicates likely pathogenic, while the Foldetta stability analysis is inconclusive and therefore not considered evidence. No contradictory evidence is present in ClinVar. Consequently, the variant is most likely pathogenic based on the available predictions, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -13.152 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 0.2 | 1.71 | Ambiguous | 1.71 | Ambiguous | 0.66 | Ambiguous | 0.903 | Likely Pathogenic | -5.48 | Deleterious | 0.996 | Probably Damaging | 0.985 | Probably Damaging | -1.29 | Pathogenic | 0.00 | Affected | 0.1883 | 0.1495 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.1808T>G | M603R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M603R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. All other evaluated predictors—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. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No other tools provide conflicting evidence. Based on the preponderance of pathogenic predictions and the absence of benign consensus, 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 | GAP | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -14.968 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.08 | Likely Benign | 0.0 | 1.13 | Ambiguous | 0.61 | Ambiguous | 0.65 | Ambiguous | 0.935 | Likely Pathogenic | -5.64 | Deleterious | 0.963 | Probably Damaging | 0.943 | Probably Damaging | -1.35 | Pathogenic | 0.00 | Affected | 0.1516 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1809G>A | M603I 2D  AIThe SynGAP1 missense variant M603I 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 Rosetta, Foldetta, and premPS, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX reports an uncertain effect. 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 benign. Overall, the balance of evidence points to a pathogenic effect for M603I, 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 | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -10.086 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.6 | 0.07 | Likely Benign | 0.44 | Likely Benign | -0.07 | Likely Benign | 0.699 | Likely Pathogenic | -3.32 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.21 | Pathogenic | 0.03 | Affected | 0.1208 | 0.2350 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1809G>C | M603I 2D AIThe SynGAP1 missense variant M603I 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 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, and AlphaMissense‑Optimized. FoldX reports an uncertain result. 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 preponderance of evidence points to a pathogenic effect for M603I. This conclusion is not contradicted by 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 | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -10.086 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.6 | 0.07 | Likely Benign | 0.44 | Likely Benign | -0.07 | Likely Benign | 0.699 | Likely Pathogenic | -3.32 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.21 | Pathogenic | 0.03 | Affected | 0.1208 | 0.2350 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1809G>T | M603I 2D AIThe SynGAP1 missense variant M603I 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 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, and AlphaMissense‑Optimized. FoldX reports an uncertain result. 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 preponderance of evidence points to a pathogenic effect for M603I. This conclusion is not contradicted by 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 | 0.011342 | Structured | 0.197847 | Uncertain | 0.942 | 0.176 | 0.000 | -10.086 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.81 | Ambiguous | 0.6 | 0.07 | Likely Benign | 0.44 | Likely Benign | -0.07 | Likely Benign | 0.698 | Likely Pathogenic | -3.32 | Deleterious | 0.833 | Possibly Damaging | 0.886 | Possibly Damaging | -1.21 | Pathogenic | 0.03 | Affected | 0.1208 | 0.2350 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.757A>C | N253H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N253H is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. No contradictory evidence is present in ClinVar. Overall, the preponderance of evidence from multiple in‑silico predictors points to a pathogenic effect for the variant, and this conclusion does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -12.199 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 0.31 | Likely Benign | 0.1 | 0.76 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | 0.832 | Likely Pathogenic | -4.39 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.51 | Benign | 0.01 | Affected | 0.1936 | 0.8033 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.757A>G | N253D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N253D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on benign effects include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicating likely pathogenic, whereas Foldetta predicts a benign effect on protein stability. Overall, the majority of tools (8/15) favor a pathogenic outcome, with no conflict with ClinVar status because the variant is not yet catalogued. Thus, the variant is most likely pathogenic based on current computational predictions, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -14.105 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.0 | 0.37 | Likely Benign | 0.31 | Likely Benign | 0.09 | Likely Benign | 0.742 | Likely Pathogenic | -4.13 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.60 | Benign | 0.09 | Tolerated | 0.2248 | 0.5186 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.757A>T | N253Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253Y is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas a larger set—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Because the majority of evidence points to a deleterious impact, the variant is most likely pathogenic; 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 | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -14.749 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 0.27 | Likely Benign | 0.1 | 1.13 | Ambiguous | 0.70 | Ambiguous | 0.29 | Likely Benign | 0.896 | Likely Pathogenic | -7.01 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 5.55 | Benign | 0.01 | Affected | 0.0642 | 0.7055 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.758A>C | N253T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253T is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy methods give a consistent pathogenic signal: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. AlphaMissense‑Optimized is uncertain and is treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect, 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 | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -11.656 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 1.96 | Ambiguous | 0.3 | 2.67 | Destabilizing | 2.32 | Destabilizing | 0.16 | Likely Benign | 0.739 | Likely Pathogenic | -5.01 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.54 | Benign | 0.06 | Tolerated | 0.1640 | 0.8665 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.758A>G | N253S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253S is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33435609‑A‑G). Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the evidence is mixed, but the single high‑accuracy tool that is available points to a benign effect. Therefore, the variant is most likely benign based on current predictions, and this assessment does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | 6-33435609-A-G | -7.197 | In-Between | 0.541 | Ambiguous | Likely Benign | 0.60 | Ambiguous | 0.1 | 1.19 | Ambiguous | 0.90 | Ambiguous | -0.03 | Likely Benign | 0.716 | Likely Pathogenic | -4.26 | Deleterious | 0.993 | Probably Damaging | 0.956 | Probably Damaging | 5.56 | Benign | 0.09 | Tolerated | 3.39 | 15 | 0.3960 | 0.7764 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||
| c.758A>T | N253I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253I is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33435609‑A‑T). Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign predictions are limited to premPS and FATHMM. High‑accuracy assessments reinforce the pathogenic 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. 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 the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | 6-33435609-A-T | 1 | 6.20e-7 | -15.241 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 2.95 | Destabilizing | 0.1 | 5.56 | Destabilizing | 4.26 | Destabilizing | 0.25 | Likely Benign | 0.836 | Likely Pathogenic | -7.83 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.57 | Benign | 0.01 | Affected | 3.39 | 15 | 0.0803 | 0.7553 | -3 | -2 | 8.0 | -0.94 | ||||||||||||||||||||||||
| c.759C>A | N253K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K resides in the PH domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM. In contrast, the majority of predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—label it pathogenic or likely pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect. This assessment is not contradicted by ClinVar, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -15.834 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.0 | 0.90 | Ambiguous | 0.48 | Likely Benign | 0.17 | Likely Benign | 0.663 | Likely Pathogenic | -5.21 | Deleterious | 0.993 | Probably Damaging | 0.979 | Probably Damaging | 5.53 | Benign | 0.03 | Affected | 0.2640 | 0.6592 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.759C>G | N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools fall into two groups: benign predictions come from FoldX, FATHMM, premPS, and Foldetta, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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, the majority of tools predict pathogenicity, and the two most reliable predictors also lean pathogenic, whereas only one high‑accuracy tool suggests benign. Therefore, 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. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -15.834 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.0 | 0.90 | Ambiguous | 0.48 | Likely Benign | 0.17 | Likely Benign | 0.663 | Likely Pathogenic | -5.21 | Deleterious | 0.993 | Probably Damaging | 0.979 | Probably Damaging | 5.53 | Benign | 0.03 | Affected | 0.2640 | 0.6592 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1825G>A | G609R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that remain uncertain are Foldetta, premPS, 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 likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) predict a pathogenic impact for G609R. 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 | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.172 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.09 | Destabilizing | 0.1 | 0.37 | Likely Benign | 1.23 | Ambiguous | 0.60 | Ambiguous | 0.520 | Likely Pathogenic | -2.68 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.41 | Pathogenic | 0.07 | Tolerated | 0.1158 | 0.4348 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1825G>C | G609R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that remain uncertain are Foldetta, premPS, 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 likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) predict a pathogenic impact for G609R. 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 | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.172 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.09 | Destabilizing | 0.1 | 0.37 | Likely Benign | 1.23 | Ambiguous | 0.60 | Ambiguous | 0.520 | Likely Pathogenic | -2.68 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.41 | Pathogenic | 0.07 | Tolerated | 0.1158 | 0.4348 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1825G>T | G609W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609W (ClinVar ID 4327030) is not found in gnomAD. Prediction tools that classify the variant as benign include premPS and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM) predict it to be pathogenic; Rosetta, 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 pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from pathogenic‑oriented tools and the SGM Consensus supports a pathogenic effect, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | 1 | -13.074 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 3.14 | Destabilizing | 0.7 | -0.87 | Ambiguous | 1.14 | Ambiguous | 0.28 | Likely Benign | 0.566 | Likely Pathogenic | -4.70 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.0935 | 0.3181 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||
| c.1826G>A | G609E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The remaining tools (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. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -10.470 | Likely Pathogenic | 0.421 | Ambiguous | Likely Benign | 2.95 | Destabilizing | 0.4 | -1.65 | Ambiguous | 0.65 | Ambiguous | 0.61 | Ambiguous | 0.531 | Likely Pathogenic | -2.28 | Neutral | 0.916 | Possibly Damaging | 0.588 | Possibly Damaging | -1.41 | Pathogenic | 0.17 | Tolerated | 0.1709 | 0.4491 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| c.1826G>C | G609A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609A 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, PROVEAN, and FATHMM. One tool, Foldetta, yields an uncertain result. 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 remains uncertain. Overall, the majority of evidence points to a benign impact. 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. | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -6.790 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 2.38 | Destabilizing | 0.3 | 0.01 | Likely Benign | 1.20 | Ambiguous | 0.43 | Likely Benign | 0.494 | Likely Benign | -2.65 | Deleterious | 0.282 | Benign | 0.164 | Benign | -1.43 | Pathogenic | 0.10 | Tolerated | 0.3812 | 0.3896 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.1826G>T | G609V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from premPS and AlphaMissense‑Optimized, whereas the remaining 10 tools (SGM Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) all predict pathogenicity. High‑accuracy assessments further highlight the discordance: AlphaMissense‑Optimized reports a benign effect, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both indicate pathogenicity. With the majority of evidence pointing to deleterious impact, 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 | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -11.049 | Likely Pathogenic | 0.374 | Ambiguous | Likely Benign | 4.17 | Destabilizing | 0.3 | 3.77 | Destabilizing | 3.97 | Destabilizing | 0.34 | Likely Benign | 0.734 | Likely Pathogenic | -4.47 | Deleterious | 0.974 | Probably Damaging | 0.818 | Possibly Damaging | -1.48 | Pathogenic | 0.02 | Affected | 0.1269 | 0.3317 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1834C>A | Q612K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612K is not reported in ClinVar (ClinVar status: not listed) and has no entry in gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and SIFT, whereas pathogenic predictions come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, 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 pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools predict pathogenicity, and the high‑accuracy consensus also leans pathogenic, while the folding‑stability method suggests benign. Thus, 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 | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -12.393 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.1 | 0.48 | Likely Benign | 0.32 | Likely Benign | 0.81 | Ambiguous | 0.619 | Likely Pathogenic | -3.88 | Deleterious | 0.931 | Possibly Damaging | 0.931 | Probably Damaging | -1.22 | Pathogenic | 0.19 | Tolerated | 0.1810 | 0.3641 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1834C>G | Q612E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). In silico predictors that agree on a benign effect include REVEL, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictors that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta are inconclusive, with Foldetta specifically yielding an uncertain stability change. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of consensus‑based and high‑accuracy predictions lean toward pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict the current 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 | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -12.179 | Likely Pathogenic | 0.338 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.4 | 1.01 | Ambiguous | 0.77 | Ambiguous | 1.03 | Destabilizing | 0.423 | Likely Benign | -2.89 | Deleterious | 0.995 | Probably Damaging | 0.981 | Probably Damaging | -1.17 | Pathogenic | 0.26 | Tolerated | 0.1393 | 0.2099 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1835A>C | Q612P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q612P is listed in ClinVar (ID 3660462.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, PolyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, PROVEAN, and the SGM Consensus score (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus predicts likely pathogenic; Foldetta, a folding‑stability method combining FoldX‑MD and Rosetta outputs, returns an uncertain result and is therefore not factored into the consensus. Overall, the majority of evidence supports a pathogenic effect, which contrasts with the ClinVar uncertain classification. Thus, based on current predictions, the variant is most likely pathogenic, contradicting the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | Uncertain | 1 | -9.684 | Likely Pathogenic | 0.673 | Likely Pathogenic | Likely Benign | -0.19 | Likely Benign | 0.3 | 3.06 | Destabilizing | 1.44 | Ambiguous | 0.56 | Ambiguous | 0.671 | Likely Pathogenic | -5.84 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.31 | Pathogenic | 0.19 | Tolerated | 0.2252 | 0.4050 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||
| c.1835A>G | Q612R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612R 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 SIFT and FoldX. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, while AlphaMissense‑Optimized and Foldetta are uncertain. No high‑accuracy tool provides a benign prediction. Overall, the majority of available evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -10.571 | Likely Pathogenic | 0.837 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.2 | 1.56 | Ambiguous | 0.61 | Ambiguous | 0.78 | Ambiguous | 0.683 | Likely Pathogenic | -3.85 | Deleterious | 0.956 | Probably Damaging | 0.969 | Probably Damaging | -1.29 | Pathogenic | 0.10 | Tolerated | 0.1480 | 0.2196 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1835A>T | Q612L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q612L 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, premPS, and SIFT, whereas those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain (unavailable), SGM Consensus as likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) as benign. Overall, the majority of conventional tools lean toward pathogenicity, and the SGM Consensus supports this, while the high‑accuracy Foldetta result is contradictory. Thus, the variant is most likely pathogenic based on the prevailing 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 | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -12.076 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | -0.12 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.00 | Likely Benign | 0.44 | Likely Benign | 0.730 | Likely Pathogenic | -6.84 | Deleterious | 0.971 | Probably Damaging | 0.954 | Probably Damaging | -1.33 | Pathogenic | 0.08 | Tolerated | 0.0763 | 0.4756 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| c.1836G>C | Q612H 2D AIThe SynGAP1 missense variant Q612H 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 Rosetta, which scores the variant as benign. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. 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 pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM Consensus confirms a likely pathogenic status, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. FoldX and premPS are inconclusive, and Foldetta is unavailable for definitive interpretation. Based on the collective predictions, 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 | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -9.733 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.70 | Ambiguous | 0.9 | 0.39 | Likely Benign | 0.55 | Ambiguous | 0.79 | Ambiguous | 0.550 | Likely Pathogenic | -4.55 | Deleterious | 0.991 | Probably Damaging | 0.986 | Probably Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.1379 | 0.3084 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.1836G>T | Q612H 2D AIThe SynGAP1 missense variant Q612H 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 Rosetta, which scores the variant as benign. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. 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 pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM Consensus confirms a likely pathogenic status, while Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. FoldX and premPS are inconclusive, and Foldetta is unavailable for definitive interpretation. Based on the collective predictions, 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 | 0.275179 | Structured | 0.203988 | Uncertain | 0.822 | 0.263 | 0.000 | -9.733 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.70 | Ambiguous | 0.9 | 0.39 | Likely Benign | 0.55 | Ambiguous | 0.79 | Ambiguous | 0.550 | Likely Pathogenic | -4.55 | Deleterious | 0.991 | Probably Damaging | 0.986 | Probably Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.1379 | 0.3084 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.760A>C | K254Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K254Q 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, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence points to a pathogenic 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 Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -12.332 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.13 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.24 | Likely Benign | 0.90 | Ambiguous | 0.737 | Likely Pathogenic | -3.04 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.91 | Benign | 0.11 | Tolerated | 0.3749 | 0.1483 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.760A>G | K254E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 13 tools (REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus) predict pathogenicity; FoldX and Foldetta are uncertain. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized indicates pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) remains uncertain. Overall, the preponderance of evidence supports a pathogenic classification for K254E, and this conclusion does not conflict with ClinVar, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -14.745 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 2.34 | Destabilizing | 1.53 | Ambiguous | 1.17 | Destabilizing | 0.860 | Likely Pathogenic | -3.27 | Deleterious | 0.970 | Probably Damaging | 0.584 | Possibly Damaging | 5.87 | Benign | 0.05 | Affected | 0.3224 | 0.1352 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.761A>C | K254T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Benign predictions are limited to SIFT and FATHMM. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic effect for K254T, 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 | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -13.793 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.51 | Ambiguous | 0.0 | 1.92 | Ambiguous | 1.22 | Ambiguous | 0.62 | Ambiguous | 0.883 | Likely Pathogenic | -5.14 | Deleterious | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 5.88 | Benign | 0.06 | Tolerated | 0.1825 | 0.2562 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.761A>G | K254R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K254R 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive 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 majority (2 benign vs. 1 pathogenic, 1 uncertain); Foldetta is uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any 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. | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -11.064 | Likely Pathogenic | 0.528 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.1 | -1.13 | Ambiguous | -0.79 | Ambiguous | 0.76 | Ambiguous | 0.604 | Likely Pathogenic | -2.36 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.81 | Benign | 0.09 | Tolerated | 0.4070 | 0.1658 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.761A>T | K254M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight the conflict: 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. No prediction or stability result is missing or inconclusive. Overall, the majority of tools and the high‑accuracy consensus lean toward a pathogenic effect, and this assessment does not contradict ClinVar status, which currently has no entry for it. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -12.832 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.35 | Likely Benign | 0.5 | 0.48 | Likely Benign | 0.07 | Likely Benign | 0.23 | Likely Benign | 0.864 | Likely Pathogenic | -5.08 | Deleterious | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 5.78 | Benign | 0.00 | Affected | 0.1073 | 0.3562 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.762G>C | K254N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254N is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The majority of other in silico predictors—REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic effect. Stability‑based methods FoldX, Rosetta, and Foldetta returned uncertain 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 unavailable. Overall, the preponderance of evidence supports a pathogenic classification, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | Uncertain | 1 | -13.306 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.73 | Ambiguous | 0.2 | 1.87 | Ambiguous | 1.30 | Ambiguous | 1.19 | Destabilizing | 0.757 | Likely Pathogenic | -4.23 | Deleterious | 0.384 | Benign | 0.070 | Benign | 5.93 | Benign | 0.01 | Affected | 3.39 | 15 | 0.3200 | 0.1488 | 1 | 0 | 0.4 | -14.07 | 215.3 | -21.0 | -1.0 | 1.7 | 0.2 | 0.3 | X | Potentially Pathogenic | The amino group of Lys254, located in an α-β loop connecting the PH and C2 domains (res. Lys251-Arg258), forms salt bridges with the carboxylate groups of Glu244 and Asp684. Since the neutral carboxamide group of the Asn254 side chain cannot form salt bridges with acidic residues, the residue swap potentially weakens the tertiary structure assembly and/or influences the loop positioning. Regardless, in both the variant and WT simulations, all hydrogen bonds formed by the residue’s side chain were broken, and the residue rotated outwards. The partially α helical conformation of the loop, which extends to a nearby α helix (res. Met414-Asn426), is dynamic, making it unclear if the mutation affects it. | ||||||||||||||||
| c.762G>T | K254N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K254N 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic” (3 pathogenic vs. 1 benign). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -13.306 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.73 | Ambiguous | 0.2 | 1.87 | Ambiguous | 1.30 | Ambiguous | 1.19 | Destabilizing | 0.757 | Likely Pathogenic | -4.23 | Deleterious | 0.384 | Benign | 0.070 | Benign | 5.93 | Benign | 0.01 | Affected | 3.39 | 15 | 0.3200 | 0.1488 | 1 | 0 | 0.4 | -14.07 | 215.3 | -21.0 | -1.0 | 1.7 | 0.2 | 0.3 | X | Potentially Pathogenic | The amino group of Lys254, located in an α-β loop connecting the PH and C2 domains (res. Lys251-Arg258), forms salt bridges with the carboxylate groups of Glu244 and Asp684. Since the neutral carboxamide group of the Asn254 side chain cannot form salt bridges with acidic residues, the residue swap potentially weakens the tertiary structure assembly and/or influences the loop positioning. Regardless, in both the variant and WT simulations, all hydrogen bonds formed by the residue’s side chain were broken, and the residue rotated outwards. The partially α helical conformation of the loop, which extends to a nearby α helix (res. Met414-Asn426), is dynamic, making it unclear if the mutation affects it. | ||||||||||||||||||
| c.1969T>A | W657R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W657R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score, which is labeled Likely Pathogenic. 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 the Foldetta stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic impact for W657R, 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 | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | -13.391 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.56 | Ambiguous | 0.2 | 1.64 | Ambiguous | 1.60 | Ambiguous | 1.29 | Destabilizing | 0.461 | Likely Benign | -11.96 | Deleterious | 0.999 | Probably Damaging | 0.964 | Probably Damaging | 3.48 | Benign | 0.07 | Tolerated | 0.4684 | 0.0000 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||
| c.1969T>C | W657R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W657R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, while pathogenic predictions are made by premPS, 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, is classified as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority of the four high‑accuracy tools) is pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. FoldX and Rosetta individually report uncertain effects on protein stability. 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 status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | -13.391 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.56 | Ambiguous | 0.2 | 1.64 | Ambiguous | 1.60 | Ambiguous | 1.29 | Destabilizing | 0.461 | Likely Benign | -11.96 | Deleterious | 0.999 | Probably Damaging | 0.964 | Probably Damaging | 3.48 | Benign | 0.07 | Tolerated | 0.4684 | 0.0000 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||
| c.1969T>G | W657G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W657G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. In contrast, the majority of other in silico predictors (AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FoldX, Rosetta, premPS, Foldetta) all 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, PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. 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 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 | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | -12.559 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 3.04 | Destabilizing | 0.2 | 2.80 | Destabilizing | 2.92 | Destabilizing | 1.28 | Destabilizing | 0.389 | Likely Benign | -11.16 | Deleterious | 0.999 | Probably Damaging | 0.941 | Probably Damaging | 3.46 | Benign | 0.15 | Tolerated | 0.4470 | 0.0885 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.1970G>C | W657S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W657S 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, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta) predict a pathogenic impact; Rosetta remains uncertain. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and 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 assessment 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. | Likely Pathogenic | GAP | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | -11.817 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.27 | Destabilizing | 0.2 | 1.87 | Ambiguous | 2.07 | Destabilizing | 1.26 | Destabilizing | 0.334 | Likely Benign | -11.82 | Deleterious | 0.999 | Probably Damaging | 0.947 | Probably Damaging | 3.52 | Benign | 0.09 | Tolerated | 0.4299 | 0.0489 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1970G>T | W657L 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant W657L is listed in ClinVar with an uncertain significance (ClinVar ID 2767440.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta predicts a benign folding‑stability change. Overall, the majority of evidence points toward a pathogenic impact, which is consistent with the ClinVar uncertain status but leans toward pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | Uncertain | 1 | -14.411 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.14 | Likely Benign | 0.1 | 0.73 | Ambiguous | 0.44 | Likely Benign | 0.87 | Ambiguous | 0.213 | Likely Benign | -10.86 | Deleterious | 0.277 | Benign | 0.078 | Benign | 3.52 | Benign | 0.14 | Tolerated | 3.39 | 24 | 0.2302 | 0.2049 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||
| c.1971G>C | W657C 2D  AISynGAP1 missense variant W657C 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 and FATHMM. Those that predict a deleterious effect are FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta reports an uncertain outcome. High‑accuracy assessments further support a damaging interpretation: 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. Overall, the preponderance of evidence indicates that W657C 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 | GAP | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | Uncertain | 1 | -12.035 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.74 | Destabilizing | 0.3 | 1.69 | Ambiguous | 2.22 | Destabilizing | 1.30 | Destabilizing | 0.463 | Likely Benign | -11.06 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 3.43 | Benign | 0.03 | Affected | 0.3834 | 0.0766 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||
| c.1971G>T | W657C 2D AIThe SynGAP1 W657C 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 are REVEL and FATHMM, whereas the majority of tools (SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Foldetta also supports pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments further reinforce a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the preponderance of evidence points to the variant being 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 | 0.030611 | Structured | 0.208729 | Uncertain | 0.941 | 0.245 | 0.000 | -12.035 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.74 | Destabilizing | 0.3 | 1.69 | Ambiguous | 2.22 | Destabilizing | 1.30 | Destabilizing | 0.463 | Likely Benign | -11.06 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 3.43 | Benign | 0.03 | Affected | 0.3834 | 0.0766 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.1828C>A | L610I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610I is listed in gnomAD (ID 6‑33440880‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM. Four tools are uncertain (FoldX, Foldetta, premPS, AlphaMissense‑Default). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores benign, the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, whereas Foldetta’s stability estimate is unavailable. Overall, the balance of evidence points to a benign effect for L610I, 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. | GAP | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | 6-33440880-C-A | 1 | 6.19e-7 | -6.362 | Likely Benign | 0.389 | Ambiguous | Likely Benign | 1.50 | Ambiguous | 0.2 | 0.18 | Likely Benign | 0.84 | Ambiguous | 0.76 | Ambiguous | 0.544 | Likely Pathogenic | -1.86 | Neutral | 0.992 | Probably Damaging | 0.997 | Probably Damaging | -1.34 | Pathogenic | 0.15 | Tolerated | 3.37 | 35 | 0.0999 | 0.3219 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||
| c.1828C>G | L610V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L610V is reported in gnomAD (ID 6‑33440880‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, while only AlphaMissense‑Optimized predicts a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized indicates benign, whereas the SGM Consensus remains pathogenic and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. With the overwhelming majority of tools predicting pathogenicity and no ClinVar evidence to contradict this, 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 | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | 6-33440880-C-G | 3 | 1.86e-6 | -11.304 | Likely Pathogenic | 0.474 | Ambiguous | Likely Benign | 2.24 | Destabilizing | 0.3 | 0.76 | Ambiguous | 1.50 | Ambiguous | 1.21 | Destabilizing | 0.740 | Likely Pathogenic | -2.86 | Deleterious | 0.985 | Probably Damaging | 0.992 | Probably Damaging | -1.46 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1515 | 0.3039 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.1828C>T | L610F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610F 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, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—all of which classify the variant as pathogenic. No tools predict a benign outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the consensus of these 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 | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -13.244 | Likely Pathogenic | 0.808 | Likely Pathogenic | Ambiguous | 6.24 | Destabilizing | 1.1 | 3.40 | Destabilizing | 4.82 | Destabilizing | 0.68 | Ambiguous | 0.782 | Likely Pathogenic | -3.92 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.52 | Pathogenic | 0.01 | Affected | 0.0834 | 0.2816 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1829T>A | L610H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610H 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 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 | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -14.573 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 4.83 | Destabilizing | 0.5 | 4.98 | Destabilizing | 4.91 | Destabilizing | 2.03 | Destabilizing | 0.927 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.59 | Pathogenic | 0.00 | Affected | 0.1067 | 0.0741 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1829T>C | L610P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610P is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classifies the substitution as pathogenic; no tool predicts a benign effect. 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 reports a pathogenic effect. Because all evidence points to a deleterious impact and there is no ClinVar entry to contradict this, 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 | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -14.863 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 6.02 | Destabilizing | 0.2 | 8.15 | Destabilizing | 7.09 | Destabilizing | 1.99 | Destabilizing | 0.934 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.59 | Pathogenic | 0.00 | Affected | 0.3599 | 0.1113 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1829T>G | L610R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610R 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. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic outcome; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Consequently, the variant is most likely pathogenic based on 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 | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -13.855 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 5.14 | Destabilizing | 0.5 | 4.60 | Destabilizing | 4.87 | Destabilizing | 1.89 | Destabilizing | 0.949 | Likely Pathogenic | -5.94 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | -1.58 | Pathogenic | 0.00 | Affected | 0.1334 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1831A>C | M611L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611L is not reported in ClinVar and is absent from gnomAD. 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 (majority vote). 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, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -6.721 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.65 | Ambiguous | 0.52 | Ambiguous | 0.56 | Ambiguous | 0.229 | Likely Benign | -1.29 | Neutral | 0.059 | Benign | 0.017 | Benign | -1.07 | Pathogenic | 0.76 | Tolerated | 0.1130 | 0.3547 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1831A>G | M611V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields an inconclusive result (two benign, two pathogenic). Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports an uncertain effect, so its result is treated as unavailable. Overall, the balance of evidence leans toward a benign impact, 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 | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.057 | Likely Pathogenic | 0.176 | Likely Benign | Likely Benign | 1.42 | Ambiguous | 0.4 | 1.56 | Ambiguous | 1.49 | Ambiguous | 0.66 | Ambiguous | 0.315 | Likely Benign | -2.06 | Neutral | 0.960 | Probably Damaging | 0.474 | Possibly Damaging | -1.04 | Pathogenic | 0.49 | Tolerated | 0.2324 | 0.2721 | 2 | 1 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||
| c.1831A>T | M611L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611L 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic, while Rosetta, Foldetta, and premPS are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the preponderance of evidence points to a benign impact for M611L, 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 | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -6.721 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.65 | Ambiguous | 0.52 | Ambiguous | 0.56 | Ambiguous | 0.229 | Likely Benign | -1.29 | Neutral | 0.059 | Benign | 0.017 | Benign | -1.07 | Pathogenic | 0.76 | Tolerated | 0.1130 | 0.3547 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1832T>A | M611K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 M611K variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. The majority of other in silico predictors (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) indicate a pathogenic effect; FoldX is uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -13.021 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 1.86 | Ambiguous | 0.6 | 2.65 | Destabilizing | 2.26 | Destabilizing | 1.65 | Destabilizing | 0.665 | Likely Pathogenic | -4.10 | Deleterious | 0.250 | Benign | 0.120 | Benign | -1.26 | Pathogenic | 0.03 | Affected | 0.1193 | 0.0688 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1832T>C | M611T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33440884‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain or inconclusive results. 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 impact, and this does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | Uncertain | 1 | 6-33440884-T-C | 1 | 6.19e-7 | -5.696 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 1.98 | Ambiguous | 0.2 | 0.94 | Ambiguous | 1.46 | Ambiguous | 0.87 | Ambiguous | 0.240 | Likely Benign | -2.40 | Neutral | 0.034 | Benign | 0.038 | Benign | -1.19 | Pathogenic | 0.29 | Tolerated | 3.37 | 35 | 0.1635 | 0.1415 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||
| c.1832T>G | M611R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M611R 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 AlphaMissense‑Optimized, polyPhen2_HumVar, and SIFT. Tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen2_HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. 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 pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is reported as uncertain. No prediction or folding result is missing; all available data are considered. Based on the overall distribution of 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 | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -11.050 | Likely Pathogenic | 0.642 | Likely Pathogenic | Likely Benign | 1.80 | Ambiguous | 0.8 | 2.00 | Destabilizing | 1.90 | Ambiguous | 1.58 | Destabilizing | 0.644 | Likely Pathogenic | -4.10 | Deleterious | 0.779 | Possibly Damaging | 0.159 | Benign | -1.21 | Pathogenic | 0.21 | Tolerated | 0.1399 | 0.0837 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.1833G>A | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is reported in gnomAD (ID 6‑33440885‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the variant’s likely effect: AlphaMissense‑Optimized classifies it as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain stability change. No folding‑stability method provides definitive evidence. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not conflict with ClinVar status, which lacks an entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | 6-33440885-G-A | 1 | 6.19e-7 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | 0.292 | Likely Benign | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 0.1009 | 0.2302 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||
| c.1833G>C | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points toward a pathogenic classification, 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 | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | 0.292 | Likely Benign | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 0.1009 | 0.2302 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.1833G>T | M611I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M611I is not reported in ClinVar and is absent from gnomAD. In silico predictors that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Predictors that classify it as pathogenic are SGM‑Consensus, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, premPS, and Foldetta) provide uncertain or unavailable results. High‑accuracy assessment shows AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic; Foldetta’s stability output is unavailable. Overall, the majority of predictions lean toward a benign 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 | 0.236433 | Structured | 0.210791 | Uncertain | 0.870 | 0.253 | 0.000 | -8.552 | Likely Pathogenic | 0.736 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.4 | 1.36 | Ambiguous | 1.41 | Ambiguous | 0.72 | Ambiguous | 0.292 | Likely Benign | -2.10 | Neutral | 0.250 | Benign | 0.091 | Benign | -1.14 | Pathogenic | 0.38 | Tolerated | 3.37 | 35 | 0.1009 | 0.2302 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||
| c.2062G>A | E688K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E688K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, FATHMM, and Foldetta, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and premPS. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts benign stability. Overall, the majority of conventional predictors and the SGM Consensus lean toward pathogenicity, and there is no conflict with ClinVar status because the variant is not yet catalogued. Thus, based on current computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -15.177 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.6 | -0.60 | Ambiguous | -0.08 | Likely Benign | 0.77 | Ambiguous | 0.469 | Likely Benign | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.2458 | 0.5518 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.2062G>C | E688Q 2D AIThe SynGAP1 missense variant E688Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic outcome: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools (premPS and AlphaMissense‑Optimized) give uncertain results and are treated as unavailable. High‑accuracy assessments further show SGM‑Consensus 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, with no ClinVar annotation 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 | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -9.419 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.17 | Likely Benign | 0.9 | 0.15 | Likely Benign | 0.16 | Likely Benign | 0.59 | Ambiguous | 0.302 | Likely Benign | -2.53 | Deleterious | 0.997 | Probably Damaging | 0.973 | Probably Damaging | 3.27 | Benign | 0.15 | Tolerated | 0.1154 | 0.5387 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.2063A>C | E688A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E688A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Foldetta, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX, Rosetta, and premPS are inconclusive. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of evidence points to a pathogenic effect for E688A. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -13.556 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.55 | Ambiguous | 0.5 | -0.53 | Ambiguous | 0.01 | Likely Benign | 0.68 | Ambiguous | 0.495 | Likely Benign | -5.55 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.3806 | 0.5296 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2063A>G | E688G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E688G has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive predictions come from Foldetta, premPS, and Rosetta. 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). Overall, the majority of reliable tools predict a deleterious effect. Therefore, 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 | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -14.338 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.17 | Destabilizing | 0.5 | 1.44 | Ambiguous | 1.81 | Ambiguous | 0.86 | Ambiguous | 0.486 | Likely Benign | -6.55 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.3059 | 0.4433 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.2063A>T | E688V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E688V missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Foldetta, premPS, and FATHMM, while pathogenic calls are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy methods give divergent results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of tools support a pathogenic effect, and there is no ClinVar entry to contradict this assessment. 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. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -14.642 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.02 | Likely Benign | 0.6 | -0.63 | Ambiguous | -0.33 | Likely Benign | 0.37 | Likely Benign | 0.532 | Likely Pathogenic | -6.62 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.19 | Benign | 0.02 | Affected | 0.0681 | 0.5831 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2064G>C | E688D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E688D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Tools that predict a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods specifically give AlphaMissense‑Optimized a pathogenic prediction, SGM‑Consensus a pathogenic prediction, and Foldetta an uncertain result. Overall, the majority of evidence points to a pathogenic impact. 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 | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -11.890 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.79 | Ambiguous | 0.5 | 0.53 | Ambiguous | 1.16 | Ambiguous | 0.91 | Ambiguous | 0.302 | Likely Benign | -2.89 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.47 | Benign | 0.08 | Tolerated | 0.1722 | 0.3492 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.2064G>T | E688D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E688D is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Tools that predict a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods specifically give: AlphaMissense‑Optimized – pathogenic; SGM‑Consensus – pathogenic; Foldetta – uncertain. Taken together, the majority of evidence points to a pathogenic impact. 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 | 0.061840 | Structured | 0.211124 | Uncertain | 0.947 | 0.223 | 0.000 | -11.890 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.79 | Ambiguous | 0.5 | 0.53 | Ambiguous | 1.16 | Ambiguous | 0.91 | Ambiguous | 0.302 | Likely Benign | -2.89 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.47 | Benign | 0.08 | Tolerated | 0.1722 | 0.3492 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.754C>A | P252T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized and the SGM‑Consensus score (Likely Pathogenic). Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; Foldetta’s stability assessment is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -11.824 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.24 | Ambiguous | 0.1 | 1.89 | Ambiguous | 1.57 | Ambiguous | 0.71 | Ambiguous | 0.828 | Likely Pathogenic | -7.35 | Deleterious | 0.384 | Benign | 0.177 | Benign | 5.78 | Benign | 0.01 | Affected | 0.1514 | 0.4842 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.754C>G | P252A 2D 3DClick to see structure in 3D Viewer AISynGAP1 P252A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: a single benign call from FATHMM, and a majority of pathogenic calls from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for P252A, 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 | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.587 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.97 | Ambiguous | 0.1 | 1.74 | Ambiguous | 1.36 | Ambiguous | 0.69 | Ambiguous | 0.831 | Likely Pathogenic | -7.35 | Deleterious | 0.941 | Possibly Damaging | 0.607 | Possibly Damaging | 5.87 | Benign | 0.03 | Affected | 0.3490 | 0.4161 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.754C>T | P252S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252S 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 (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Predictions that are uncertain (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. 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 evidence strongly favors a pathogenic effect for P252S, 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 | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.926 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.1 | 1.81 | Ambiguous | 1.29 | Ambiguous | 0.79 | Ambiguous | 0.840 | Likely Pathogenic | -7.35 | Deleterious | 0.941 | Possibly Damaging | 0.531 | Possibly Damaging | 5.79 | Benign | 0.05 | Affected | 0.3508 | 0.4361 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.755C>A | P252H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments 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 stability outputs, is uncertain. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence indicates that P252H is most likely pathogenic, and 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 | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -11.991 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.06 | Ambiguous | 0.2 | 1.96 | Ambiguous | 1.51 | Ambiguous | 0.82 | Ambiguous | 0.845 | Likely Pathogenic | -8.27 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.1592 | 0.4128 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.755C>G | P252R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that classify the variant as benign are FoldX and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Predictions that are inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that P252R 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 | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -14.648 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.23 | Ambiguous | 0.82 | Ambiguous | 0.81 | Ambiguous | 0.890 | Likely Pathogenic | -8.27 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.80 | Benign | 0.00 | Affected | 0.1413 | 0.2848 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.755C>T | P252L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign are premPS and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute to the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, 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 | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.181 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.93 | Ambiguous | 0.0 | 1.56 | Ambiguous | 1.25 | Ambiguous | 0.47 | Likely Benign | 0.794 | Likely Pathogenic | -9.19 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0.2027 | 0.6475 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.1927G>A | E643K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic calls arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain results. High‑accuracy assessments focus on AlphaMissense‑Optimized (Uncertain), SGM‑Consensus (Likely Pathogenic), and Foldetta (Uncertain). Because the consensus of the most reliable predictors leans toward pathogenicity, 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 | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -14.318 | Likely Pathogenic | 0.868 | Likely Pathogenic | Ambiguous | 0.39 | Likely Benign | 0.2 | 1.44 | Ambiguous | 0.92 | Ambiguous | 0.82 | Ambiguous | 0.449 | Likely Benign | -3.79 | Deleterious | 0.042 | Benign | 0.004 | Benign | 2.95 | Benign | 0.04 | Affected | 0.2961 | 0.6269 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1927G>C | E643Q 2D AIThe SynGAP1 missense variant E643Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, 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. AlphaMissense‑Optimized predicts a benign outcome, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions (8 benign vs. 5 pathogenic) and the two of three high‑accuracy tools favor a benign classification. Thus, 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 Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.404 | Likely Pathogenic | 0.688 | Likely Pathogenic | Likely Benign | 0.49 | Likely Benign | 0.6 | 0.15 | Likely Benign | 0.32 | Likely Benign | 0.83 | Ambiguous | 0.341 | Likely Benign | -2.86 | Deleterious | 0.446 | Benign | 0.038 | Benign | 2.94 | Benign | 0.01 | Affected | 0.1603 | 0.6308 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1928A>C | E643A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643A 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, Rosetta, premPS, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta 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 remains uncertain. Overall, the majority of tools 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. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.562 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 0.80 | Ambiguous | 0.2 | 0.39 | Likely Benign | 0.60 | Ambiguous | 0.21 | Likely Benign | 0.469 | Likely Benign | -5.81 | Deleterious | 0.771 | Possibly Damaging | 0.233 | Benign | 2.92 | Benign | 0.01 | Affected | 0.4074 | 0.6096 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1928A>G | E643G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default; FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta’s stability prediction is uncertain. Overall, the majority of reliable tools predict pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. 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 | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.503 | Likely Pathogenic | 0.707 | Likely Pathogenic | Likely Benign | 1.45 | Ambiguous | 0.3 | 2.06 | Destabilizing | 1.76 | Ambiguous | 1.01 | Destabilizing | 0.520 | Likely Pathogenic | -6.81 | Deleterious | 0.983 | Probably Damaging | 0.390 | Benign | 2.94 | Benign | 0.00 | Affected | 0.2821 | 0.5319 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1928A>T | E643V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E643V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from Rosetta, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Three tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic (3 pathogenic vs. 1 benign). AlphaMissense‑Optimized remains uncertain, and Foldetta also yields an uncertain stability change. Overall, the preponderance of evidence points to a pathogenic effect for E643V, and this conclusion does not contradict any existing ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.975 | Likely Pathogenic | 0.893 | Likely Pathogenic | Ambiguous | 1.13 | Ambiguous | 0.1 | -0.06 | Likely Benign | 0.54 | Ambiguous | -0.28 | Likely Benign | 0.554 | Likely Pathogenic | -6.85 | Deleterious | 0.727 | Possibly Damaging | 0.145 | Benign | 2.89 | Benign | 0.00 | Affected | 0.0948 | 0.6637 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1929G>C | E643D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643D 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, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen2_HumVar. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen2_HumDiv, SIFT, and ESM1b. 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 (8 benign vs. 5 pathogenic) support 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 | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -8.083 | Likely Pathogenic | 0.223 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.2 | -0.34 | Likely Benign | 0.06 | Likely Benign | 1.09 | Destabilizing | 0.292 | Likely Benign | -2.96 | Deleterious | 0.694 | Possibly Damaging | 0.064 | Benign | 2.98 | Benign | 0.01 | Affected | 0.2040 | 0.4276 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1929G>T | E643D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643D 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, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen2_HumVar. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen2_HumDiv, SIFT, and ESM1b. 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 (8 benign vs. 5 pathogenic) support 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 | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -8.083 | Likely Pathogenic | 0.223 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.2 | -0.34 | Likely Benign | 0.06 | Likely Benign | 1.09 | Destabilizing | 0.292 | Likely Benign | -2.96 | Deleterious | 0.694 | Possibly Damaging | 0.064 | Benign | 2.98 | Benign | 0.01 | Affected | 0.2040 | 0.4276 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.763G>A | D255N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include 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. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains inconclusive. Overall, the consensus of the available predictions points to a pathogenic effect for D255N, and 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 | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -12.251 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.17 | Ambiguous | 0.38 | Likely Benign | 0.682 | Likely Pathogenic | -4.30 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.84 | Benign | 0.01 | Affected | 0.1117 | 0.4774 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.763G>C | D255H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of the available predictions points to a pathogenic effect for D255H, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -14.645 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.2 | 1.17 | Ambiguous | 1.45 | Ambiguous | 0.44 | Likely Benign | 0.808 | Likely Pathogenic | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.1447 | 0.5211 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||
| c.763G>T | D255Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255Y 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 premPS and FATHMM, while 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. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion 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 | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -13.180 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.25 | Ambiguous | 0.2 | 0.96 | Ambiguous | 1.11 | Ambiguous | 0.13 | Likely Benign | 0.832 | Likely Pathogenic | -7.77 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 5.73 | Benign | 0.00 | Affected | 0.0464 | 0.5178 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||
| c.764A>C | D255A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D255A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” vote) predict a pathogenic impact. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute evidence. 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. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -11.789 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.48 | Ambiguous | 0.2 | 1.04 | Ambiguous | 1.26 | Ambiguous | 0.35 | Likely Benign | 0.829 | Likely Pathogenic | -6.85 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.80 | Benign | 0.01 | Affected | 0.3363 | 0.4805 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||
| c.764A>G | D255G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D255G 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 premPS and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are therefore not used as evidence. 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. 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 | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -12.652 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.1 | 1.34 | Ambiguous | 1.53 | Ambiguous | 0.31 | Likely Benign | 0.885 | Likely Pathogenic | -6.13 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 5.86 | Benign | 0.01 | Affected | 0.3211 | 0.5185 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.764A>T | D255V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of available predictions points to a pathogenic effect for D255V, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -13.575 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.76 | Ambiguous | 0.2 | 1.07 | Ambiguous | 1.42 | Ambiguous | 0.16 | Likely Benign | 0.895 | Likely Pathogenic | -7.77 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | 0.0684 | 0.5162 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||
| c.765C>A | D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change D255E 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 premPS, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions (seven pathogenic vs. four benign) point to a likely pathogenic impact. 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. | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -6.876 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.90 | Ambiguous | 0.85 | Ambiguous | 0.15 | Likely Benign | 0.508 | Likely Pathogenic | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.89 | Benign | 0.08 | Tolerated | 0.1365 | 0.5067 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||
| c.765C>G | D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255E 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 premPS, SIFT, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The remaining tools (FoldX, Rosetta, Foldetta) provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta is also inconclusive. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) indicate a pathogenic effect. Thus, 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. | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -6.876 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.90 | Ambiguous | 0.85 | Ambiguous | 0.15 | Likely Benign | 0.509 | Likely Pathogenic | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.89 | Benign | 0.08 | Tolerated | 0.1365 | 0.5067 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||
| 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 | -0.05 | Likely Benign | 0.2 | 0.34 | Likely Benign | 0.15 | Likely Benign | 0.81 | Ambiguous | 0.310 | Likely Benign | -1.99 | Neutral | 0.879 | Possibly Damaging | 0.985 | Probably Damaging | 3.31 | Benign | 0.12 | Tolerated | 0.0767 | 0.2678 | 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 | 1.39 | Ambiguous | 0.0 | 0.44 | Likely Benign | 0.92 | Ambiguous | 0.89 | Ambiguous | 0.173 | Likely Benign | -0.79 | Neutral | 0.914 | Possibly Damaging | 0.960 | Probably Damaging | 3.15 | Benign | 0.13 | Tolerated | 3.37 | 35 | 0.0939 | 0.2130 | 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 | 2.35 | Destabilizing | 0.3 | 3.74 | Destabilizing | 3.05 | Destabilizing | 0.93 | Ambiguous | 0.601 | Likely Pathogenic | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.993 | Probably Damaging | 2.89 | Benign | 0.00 | Affected | 3.37 | 35 | 0.0574 | 0.1629 | 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 | 3.41 | Destabilizing | 0.3 | 2.41 | Destabilizing | 2.91 | Destabilizing | 2.61 | Destabilizing | 0.582 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.0770 | 0.0142 | -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 | 2.92 | Destabilizing | 0.1 | 1.88 | Ambiguous | 2.40 | Destabilizing | 1.94 | Destabilizing | 0.617 | Likely Pathogenic | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.0962 | 0.0480 | 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 | 4.03 | Destabilizing | 0.2 | 3.70 | Destabilizing | 3.87 | Destabilizing | 2.11 | Destabilizing | 0.625 | Likely Pathogenic | -5.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.82 | Benign | 0.00 | Affected | 0.2296 | 0.0530 | -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 | 0.48 | Likely Benign | 0.2 | 0.78 | Ambiguous | 0.63 | Ambiguous | 1.13 | Destabilizing | 0.335 | Likely Benign | -2.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.88 | Benign | 0.00 | Affected | 0.0647 | 0.1816 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.751A>C | K251Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, 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 polyPhen‑2 HumVar, while premPS and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence supports a benign classification for K251Q, and this conclusion does not contradict the absence of a ClinVar entry. Based on the aggregate predictions, K251Q is most likely benign, and this is consistent with its absence from ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -5.869 | Likely Benign | 0.362 | Ambiguous | Likely Benign | 0.36 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.39 | Likely Benign | -0.62 | Ambiguous | 0.465 | Likely Benign | 0.55 | Neutral | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.86 | Benign | 0.63 | Tolerated | 0.4466 | 0.1085 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.751A>G | K251E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K251E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, with a small but notable benign signal. Therefore, the variant is most likely pathogenic based on 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. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -12.812 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.88 | Ambiguous | 0.2 | 0.99 | Ambiguous | 0.94 | Ambiguous | 0.40 | Likely Benign | 0.571 | Likely Pathogenic | -0.54 | Neutral | 0.970 | Probably Damaging | 0.584 | Possibly Damaging | 5.80 | Benign | 0.46 | Tolerated | 0.3929 | 0.0860 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||
| c.752A>C | K251T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251T 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, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic prediction, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the balance of evidence favors a pathogenic effect for K251T, 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 | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -10.552 | Likely Pathogenic | 0.841 | Likely Pathogenic | Ambiguous | 1.21 | Ambiguous | 0.4 | 0.50 | Ambiguous | 0.86 | Ambiguous | 0.46 | Likely Benign | 0.742 | Likely Pathogenic | -2.72 | Deleterious | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 5.76 | Benign | 0.28 | Tolerated | 0.2353 | 0.2852 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.752A>G | K251R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Rosetta and Foldetta give uncertain results. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. 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, 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 | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -4.355 | Likely Benign | 0.123 | Likely Benign | Likely Benign | -0.37 | Likely Benign | 0.0 | -0.64 | Ambiguous | -0.51 | Ambiguous | 0.14 | Likely Benign | 0.531 | Likely Pathogenic | -0.61 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.92 | Benign | 0.34 | Tolerated | 0.4756 | 0.1049 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.752A>T | K251M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K251M 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 FoldX, Rosetta, Foldetta, premPS, PROVEAN, and FATHMM. Those that predict pathogenicity are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a benign effect. Overall, the evidence is evenly split between benign and pathogenic predictions, with the most reliable high‑accuracy tools leaning toward a benign outcome. Thus, the variant is most likely benign 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. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -10.678 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.14 | Likely Benign | 0.1 | 0.10 | Likely Benign | 0.12 | Likely Benign | 0.05 | Likely Benign | 0.751 | Likely Pathogenic | -2.36 | Neutral | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 5.73 | Benign | 0.05 | Affected | 0.1271 | 0.3475 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||
| c.753G>C | K251N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251N 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM (nine tools). Only AlphaMissense‑Default predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the preponderance of evidence indicates that K251N is most likely benign, 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. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -7.978 | In-Between | 0.930 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.25 | Likely Benign | 0.32 | Likely Benign | 0.298 | Likely Benign | -1.29 | Neutral | 0.384 | Benign | 0.070 | Benign | 5.73 | Benign | 0.39 | Tolerated | 0.3848 | 0.1196 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.753G>T | K251N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251N 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM (nine tools). Only AlphaMissense‑Default predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the preponderance of evidence indicates that K251N is most likely benign, 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. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -7.978 | In-Between | 0.930 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.25 | Likely Benign | 0.32 | Likely Benign | 0.298 | Likely Benign | -1.29 | Neutral | 0.384 | Benign | 0.070 | Benign | 5.73 | Benign | 0.39 | Tolerated | 0.3848 | 0.1196 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.2065C>A | L689I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689I 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, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar, while those that predict a pathogenic effect are polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also unavailable. No folding‑stability evidence supports a deleterious change. Overall, the balance of evidence slightly favors a benign interpretation, 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 | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -11.196 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 1.71 | Ambiguous | 0.1 | 1.12 | Ambiguous | 1.42 | Ambiguous | 0.85 | Ambiguous | 0.180 | Likely Benign | -1.97 | Neutral | 0.822 | Possibly Damaging | 0.381 | Benign | 3.44 | Benign | 0.00 | Affected | 0.0921 | 0.3479 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.2065C>G | L689V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689V 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, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) and the SGM Consensus (Likely Pathogenic) predict a pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM Consensus is Likely Pathogenic; Foldetta predicts a pathogenic effect. Taken together, the preponderance of evidence points to a pathogenic effect for L689V. This conclusion is not contradicted by 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 | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -11.387 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 2.98 | Destabilizing | 0.1 | 2.25 | Destabilizing | 2.62 | Destabilizing | 1.32 | Destabilizing | 0.234 | Likely Benign | -2.97 | Deleterious | 0.926 | Possibly Damaging | 0.481 | Possibly Damaging | 3.27 | Benign | 0.00 | Affected | 0.1393 | 0.3189 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2065C>T | L689F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689F 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. Two tools (Rosetta and premPS) yield uncertain results. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus 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 preponderance 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 | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -9.817 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 2.45 | Destabilizing | 0.2 | 1.95 | Ambiguous | 2.20 | Destabilizing | 0.67 | Ambiguous | 0.286 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.860 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 0.0608 | 0.2891 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2066T>A | L689H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689H 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 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 agreement among 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 | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -14.659 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.40 | Destabilizing | 0.1 | 2.50 | Destabilizing | 2.95 | Destabilizing | 2.21 | Destabilizing | 0.532 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.14 | Benign | 0.00 | Affected | 0.1013 | 0.0456 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.2066T>C | L689P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689P 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 | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -17.900 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.76 | Destabilizing | 0.2 | 13.35 | Destabilizing | 10.06 | Destabilizing | 2.29 | Destabilizing | 0.631 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.3668 | 0.1353 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2066T>G | L689R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L689R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge 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 indicate pathogenicity, whereas only FATHMM predicts a benign outcome. 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. No predictions are missing or inconclusive. 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 | 0.042364 | Structured | 0.227227 | Uncertain | 0.963 | 0.248 | 0.000 | -17.776 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.91 | Destabilizing | 0.6 | 5.61 | Destabilizing | 5.76 | Destabilizing | 2.14 | Destabilizing | 0.609 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.932 | Probably Damaging | 3.15 | Benign | 0.00 | Affected | 0.1208 | 0.0530 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.766A>C | N256H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256H is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The 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 evidence points to a pathogenic effect, 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 | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -8.090 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.56 | Ambiguous | 0.3 | 0.26 | Likely Benign | 0.41 | Likely Benign | 0.08 | Likely Benign | 0.698 | Likely Pathogenic | -4.06 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.82 | Benign | 0.05 | Affected | 0.1233 | 0.5646 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.766A>G | N256D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N256D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta, Foldetta, premPS, and FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. FoldX is uncertain and therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the overall consensus leans toward a pathogenic effect, with 10 tools supporting pathogenicity versus 4 supporting benignity. This conclusion is not contradicted by 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 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -12.478 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.3 | 0.21 | Likely Benign | 0.45 | Likely Benign | 0.44 | Likely Benign | 0.701 | Likely Pathogenic | -4.36 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 5.81 | Benign | 0.03 | Affected | 0.1890 | 0.3514 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.766A>T | N256Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label it pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the preponderance of evidence from standard predictors and the two high‑accuracy pathogenic calls suggests that 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 | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -10.881 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.17 | Likely Benign | 0.2 | -0.80 | Ambiguous | -0.32 | Likely Benign | 0.30 | Likely Benign | 0.868 | Likely Pathogenic | -6.85 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.83 | Benign | 0.00 | Affected | 0.0493 | 0.5881 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.767A>C | N256T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while the Foldetta stability assessment reports a benign effect. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points to a pathogenic effect, 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 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -12.212 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.88 | Ambiguous | 0.1 | -0.18 | Likely Benign | 0.35 | Likely Benign | 0.49 | Likely Benign | 0.819 | Likely Pathogenic | -5.25 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 5.85 | Benign | 0.01 | Affected | 0.1249 | 0.5848 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.767A>G | N256S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256S is listed in ClinVar as Pathogenic (ClinVar ID 2584352.0) and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy subset gives 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 Benign. Overall, the majority of predictions support a pathogenic effect, aligning with the ClinVar classification. Therefore, 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 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | Likely Pathogenic | 1 | -10.640 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.31 | Likely Benign | 0.2 | 0.36 | Likely Benign | 0.34 | Likely Benign | 0.48 | Likely Benign | 0.707 | Likely Pathogenic | -4.33 | Deleterious | 0.997 | Probably Damaging | 0.970 | Probably Damaging | 5.87 | Benign | 0.02 | Affected | 3.39 | 15 | 0.3024 | 0.5864 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||
| c.767A>T | N256I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect, 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 | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -14.050 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.64 | Ambiguous | 0.4 | 0.45 | Likely Benign | 0.55 | Ambiguous | 0.31 | Likely Benign | 0.849 | Likely Pathogenic | -7.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.87 | Benign | 0.00 | Affected | 0.0596 | 0.6260 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.768C>A | N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 favor a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this assessment 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 | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -13.814 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | -0.10 | Likely Benign | 0.06 | Likely Benign | 0.55 | Ambiguous | 0.569 | Likely Pathogenic | -5.02 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.90 | Benign | 0.01 | Affected | 0.1702 | 0.5240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.768C>G | N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 support a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and 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 | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -13.814 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | -0.10 | Likely Benign | 0.06 | Likely Benign | 0.55 | Ambiguous | 0.569 | Likely Pathogenic | -5.02 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.90 | Benign | 0.01 | Affected | 0.1702 | 0.5240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1966G>A | E656K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E656K has no ClinVar entry and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” FoldX and Foldetta return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment 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 | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -13.833 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -1.06 | Ambiguous | 0.0 | 0.02 | Likely Benign | -0.52 | Ambiguous | 0.16 | Likely Benign | 0.502 | Likely Pathogenic | -3.49 | Deleterious | 0.985 | Probably Damaging | 0.553 | Possibly Damaging | 3.44 | Benign | 0.03 | Affected | 0.3001 | 0.6406 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1966G>C | E656Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E656Q is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33441225‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default; Rosetta reports an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑2 split. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | Uncertain | 1 | 6-33441225-G-C | 1 | 6.20e-7 | -9.145 | Likely Pathogenic | 0.766 | Likely Pathogenic | Likely Benign | -0.14 | Likely Benign | 0.0 | -0.81 | Ambiguous | -0.48 | Likely Benign | 0.25 | Likely Benign | 0.249 | Likely Benign | -2.29 | Neutral | 0.980 | Probably Damaging | 0.528 | Possibly Damaging | 3.46 | Benign | 0.02 | Affected | 3.39 | 24 | 0.1739 | 0.6645 | 2 | 2 | 0.0 | -0.98 | 224.3 | 1.7 | 0.0 | 0.1 | 0.1 | 0.0 | X | Potentially Benign | The carboxylate side chain of Glu656, located on an α helix (res. Ser641-Glu666), frequently forms a hydrogen bond with the nearby residue Ser659 on the same α helix. In the variant simulations, the carboxamide side chain of Gln656 alternatively forms a hydrogen bond with either Ser659 or Glu548 on an opposing helix (res. Ala533-Val560).Although the frequent interaction between Gln656 and Glu548 may strengthen or stabilize the tertiary structure assembly, the effect is likely to be marginal. | ||||||||||||||
| c.1967A>C | E656A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E656A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 reveal that AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No prediction or stability result is missing or inconclusive. Based on the overall evidence, the variant is most likely pathogenic; this assessment does not contradict ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -14.373 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.12 | Likely Benign | 0.0 | 0.10 | Likely Benign | 0.11 | Likely Benign | -0.13 | Likely Benign | 0.499 | Likely Benign | -5.38 | Deleterious | 0.985 | Probably Damaging | 0.755 | Possibly Damaging | 3.46 | Benign | 0.03 | Affected | 0.4244 | 0.6271 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1967A>G | E656G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E656G missense variant has no ClinVar entry and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Only premPS and FATHMM predict a benign outcome, while FoldX and Foldetta are inconclusive. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E656G, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -14.112 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.1 | 2.02 | Destabilizing | 1.49 | Ambiguous | 0.22 | Likely Benign | 0.534 | Likely Pathogenic | -6.28 | Deleterious | 1.000 | Probably Damaging | 0.941 | Probably Damaging | 3.44 | Benign | 0.05 | Affected | 0.3216 | 0.5208 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1967A>T | E656V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E656V has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, 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) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of tools (8 of 13) indicate a pathogenic impact, 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 | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -15.252 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.26 | Likely Benign | 0.0 | -0.10 | Likely Benign | -0.18 | Likely Benign | -0.77 | Ambiguous | 0.509 | Likely Pathogenic | -6.38 | Deleterious | 0.784 | Possibly Damaging | 0.223 | Benign | 3.46 | Benign | 0.02 | Affected | 0.0990 | 0.7057 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1968A>C | E656D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E656D has no ClinVar entry and is not reported in gnomAD. Prediction tools show mixed results: benign predictions come from REVEL, FoldX, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates 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 Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. No evidence from Foldetta or Rosetta is available to refute pathogenicity. Overall, the majority of high‑confidence tools predict a pathogenic impact, and this is consistent with the absence of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -11.992 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.1 | 1.02 | Ambiguous | 0.62 | Ambiguous | 0.39 | Likely Benign | 0.275 | Likely Benign | -2.72 | Deleterious | 0.985 | Probably Damaging | 0.426 | Benign | 3.41 | Benign | 0.06 | Tolerated | 0.2052 | 0.4120 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1968A>T | E656D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E656D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign calls (REVEL, FoldX, premPS, polyPhen‑2 HumVar, SIFT, FATHMM) and pathogenic calls (PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized). The SGM‑Consensus score is “Likely Pathogenic,” while Foldetta and Rosetta outputs are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, 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 | 0.032017 | Structured | 0.242242 | Uncertain | 0.963 | 0.264 | 0.000 | -11.992 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.1 | 1.02 | Ambiguous | 0.62 | Ambiguous | 0.39 | Likely Benign | 0.273 | Likely Benign | -2.72 | Deleterious | 0.985 | Probably Damaging | 0.426 | Benign | 3.41 | Benign | 0.06 | Tolerated | 0.2052 | 0.4120 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.748G>A | V250I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V250I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the change 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). The high‑accuracy tools likewise predict a benign effect: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -6.696 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.44 | Likely Benign | 0.1 | -0.01 | Likely Benign | -0.23 | Likely Benign | 0.35 | Likely Benign | 0.362 | Likely Benign | -0.79 | Neutral | 0.384 | Benign | 0.070 | Benign | 6.09 | Benign | 0.13 | Tolerated | 0.0571 | 0.3644 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.748G>C | V250L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L 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 FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward 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. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.649 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | -0.23 | Likely Benign | 0.1 | 2.47 | Destabilizing | 1.12 | Ambiguous | 0.66 | Ambiguous | 0.690 | Likely Pathogenic | -2.47 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 5.81 | Benign | 0.04 | Affected | 0.0698 | 0.4229 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.748G>T | V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L 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 FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward 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. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.649 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | -0.23 | Likely Benign | 0.1 | 2.47 | Destabilizing | 1.12 | Ambiguous | 0.66 | Ambiguous | 0.690 | Likely Pathogenic | -2.47 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 5.81 | Benign | 0.04 | Affected | 0.0698 | 0.4229 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.749T>A | V250E 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant V250E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, whereas the remaining 12 tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction or stability result is inconclusive. Consequently, the variant is most likely pathogenic, 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 | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -15.723 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.85 | Ambiguous | 0.1 | 3.34 | Destabilizing | 2.60 | Destabilizing | 2.01 | Destabilizing | 0.906 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.74 | Benign | 0.00 | Affected | 0.0787 | 0.1564 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.749T>C | V250A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V250A missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a pathogenic effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all indicate pathogenicity, whereas ESM1b and FATHMM predict a benign outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) and AlphaMissense‑Optimized return uncertain results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is balanced and therefore unavailable, and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V250A, and this assessment 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. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -6.385 | Likely Benign | 0.852 | Likely Pathogenic | Ambiguous | 0.82 | Ambiguous | 0.1 | 1.22 | Ambiguous | 1.02 | Ambiguous | 1.48 | Destabilizing | 0.818 | Likely Pathogenic | -3.11 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 5.82 | Benign | 0.02 | Affected | 0.2491 | 0.2151 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.749T>G | V250G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V250G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates a pathogenic effect. 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. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.255 | Likely Pathogenic | 0.917 | Likely Pathogenic | Ambiguous | 1.65 | Ambiguous | 0.3 | 3.18 | Destabilizing | 2.42 | Destabilizing | 2.08 | Destabilizing | 0.900 | Likely Pathogenic | -5.90 | Deleterious | 0.879 | Possibly Damaging | 0.997 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | 0.1884 | 0.1996 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| 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 | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | 0.416 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.1307 | 0.4104 | -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 | 1.94 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.63 | Ambiguous | 0.94 | Ambiguous | 0.415 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 3.37 | 35 | 0.1307 | 0.4104 | -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 | 2.17 | Destabilizing | 0.2 | 2.62 | Destabilizing | 2.40 | Destabilizing | 1.15 | Destabilizing | 0.479 | Likely Benign | -7.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 0.1882 | 0.4240 | 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 | 0.80 | Ambiguous | 0.2 | 0.25 | Likely Benign | 0.53 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.23 | Benign | 0.02 | Affected | 0.3793 | 0.2778 | 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 | 3.47 | Destabilizing | 0.2 | 0.79 | Ambiguous | 2.13 | Destabilizing | 0.65 | Ambiguous | 0.540 | Likely Pathogenic | -8.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.01 | Affected | 0.1557 | 0.3019 | -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 | 0.17 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.40 | Likely Benign | -0.03 | Likely Benign | 0.344 | Likely Benign | -3.85 | Deleterious | 0.962 | Probably Damaging | 0.658 | Possibly Damaging | 3.32 | Benign | 0.06 | Tolerated | 0.2844 | 0.4776 | 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 | 0.09 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.26 | Likely Benign | 0.00 | Likely Benign | 0.283 | Likely Benign | -2.86 | Deleterious | 0.947 | Possibly Damaging | 0.706 | Possibly Damaging | 3.32 | Benign | 0.14 | Tolerated | 0.1523 | 0.4815 | 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 | 0.45 | Likely Benign | 0.1 | 0.97 | Ambiguous | 0.71 | Ambiguous | 0.04 | Likely Benign | 0.309 | Likely Benign | -5.71 | Deleterious | 0.987 | Probably Damaging | 0.937 | Probably Damaging | 3.31 | Benign | 0.12 | Tolerated | 0.4293 | 0.5162 | 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 | 0.86 | Ambiguous | 0.1 | 1.84 | Ambiguous | 1.35 | Ambiguous | 0.17 | Likely Benign | 0.381 | Likely Benign | -6.46 | Deleterious | 0.997 | Probably Damaging | 0.915 | Probably Damaging | 3.30 | Benign | 0.02 | Affected | 0.3262 | 0.4185 | 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 | 0.72 | Ambiguous | 0.1 | 1.00 | Ambiguous | 0.86 | Ambiguous | 0.14 | Likely Benign | 0.439 | Likely Benign | -6.71 | Deleterious | 0.989 | Probably Damaging | 0.854 | Possibly Damaging | 3.23 | Benign | 0.01 | Affected | 0.0994 | 0.4884 | -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 | 0.12 | Likely Benign | 0.3 | 1.05 | Ambiguous | 0.59 | Ambiguous | 0.00 | Likely Benign | 0.259 | Likely Benign | -2.10 | Neutral | 0.016 | Benign | 0.012 | Benign | 3.34 | Benign | 0.23 | Tolerated | 0.2055 | 0.3089 | 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 | 0.12 | Likely Benign | 0.3 | 1.05 | Ambiguous | 0.59 | Ambiguous | 0.00 | Likely Benign | 0.259 | Likely Benign | -2.10 | Neutral | 0.016 | Benign | 0.012 | Benign | 3.34 | Benign | 0.23 | Tolerated | 0.2055 | 0.3089 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.2068T>A | S690T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and polyPhen‑2 HumVar, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive (FoldX, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence leans toward pathogenicity, and this conclusion 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 | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -11.380 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.39 | Likely Benign | 0.67 | Ambiguous | 0.311 | Likely Benign | -2.84 | Deleterious | 0.943 | Possibly Damaging | 0.267 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1059 | 0.4674 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2068T>C | S690P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: 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 predictions, also classifies the variant as pathogenic. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, a conclusion that 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 | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | Uncertain | 1 | -14.568 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.3 | 4.40 | Destabilizing | 4.62 | Destabilizing | 1.42 | Destabilizing | 0.431 | Likely Benign | -4.77 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.44 | Benign | 0.01 | Affected | 3.42 | 17 | 0.1787 | 0.4050 | 1 | -1 | -0.8 | 10.04 | 207.5 | 15.1 | 0.1 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl side chain of Ser690, located in an α-helix (res. Leu696-Leu685), forms a hydrogen bond with the backbone carbonyl group of Ser410 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399). In the variant simulations, the pyrrolidine side chain of Pro690 cannot form hydrogen bonds with the C2 domain residue, resulting in the loss of this inter-domain connection. Additionally, prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Gly686, introducing a slight bend in the α-helix and compromising its integrity. | |||||||||||||||
| c.2068T>G | S690A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta reports an uncertain stability change, so these results are treated as unavailable. Overall, the balance of evidence favors a benign interpretation, 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. | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -8.763 | Likely Pathogenic | 0.318 | Likely Benign | Likely Benign | -0.82 | Ambiguous | 0.0 | -2.17 | Stabilizing | -1.50 | Ambiguous | 0.45 | Likely Benign | 0.217 | Likely Benign | -2.55 | Deleterious | 0.887 | Possibly Damaging | 0.738 | Possibly Damaging | 3.45 | Benign | 0.21 | Tolerated | 0.4619 | 0.3131 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||
| c.2069C>A | S690Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus confirms a Likely Pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the absence of benign consensus, the variant is most likely pathogenic, with no contradiction to 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 | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -14.051 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 11.45 | Destabilizing | 3.1 | 3.02 | Destabilizing | 7.24 | Destabilizing | 0.16 | Likely Benign | 0.381 | Likely Benign | -5.76 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.39 | Benign | 0.00 | Affected | 0.0512 | 0.4643 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.2069C>G | S690C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690C is not reported in ClinVar and has no gnomAD entry. Consensus predictions from high‑accuracy tools show a split: AlphaMissense‑Optimized rates it benign, whereas the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, also predicts a benign effect. In contrast, the broader set of in silico predictors is divided: benign calls come from REVEL, FoldX, Rosetta, Foldetta, and FATHMM; pathogenic calls arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The premPS score is uncertain. Overall, the majority of tools (seven pathogenic vs. six benign) lean toward a pathogenic interpretation, but the presence of strong benign evidence from several high‑confidence methods tempers this conclusion. Thus, the variant is most likely pathogenic, 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 | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -10.651 | Likely Pathogenic | 0.749 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.33 | Likely Benign | 0.82 | Ambiguous | 0.358 | Likely Benign | -4.69 | Deleterious | 0.999 | Probably Damaging | 0.944 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.0787 | 0.4612 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.2069C>T | S690F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690F 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 predict a pathogenic outcome: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are inconclusive or missing. 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 | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -14.325 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 9.85 | Destabilizing | 2.4 | 2.17 | Destabilizing | 6.01 | Destabilizing | 0.51 | Ambiguous | 0.384 | Likely Benign | -5.76 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.39 | Benign | 0.00 | Affected | 0.0498 | 0.4800 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1930G>A | D644N 2D AIThe SynGAP1 missense variant D644N 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 and HumVar), SIFT, ESM1b, and FATHMM—all classifying the substitution as benign. No tool predicts pathogenicity. The only inconclusive result is AlphaMissense‑Default, which is listed as uncertain and therefore does not influence the overall assessment. High‑accuracy methods further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. 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 | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -4.389 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.06 | Likely Benign | 0.3 | -0.28 | Likely Benign | -0.11 | Likely Benign | 0.02 | Likely Benign | 0.124 | Likely Benign | -2.28 | Neutral | 0.007 | Benign | 0.001 | Benign | 3.45 | Benign | 0.25 | Tolerated | 0.1368 | 0.6261 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1930G>C | D644H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D644H 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, Foldetta, premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, 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 due to a 2‑vs‑2 split. No other high‑accuracy predictions are 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. | GAP | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -6.786 | Likely Benign | 0.771 | Likely Pathogenic | Likely Benign | 0.34 | Likely Benign | 0.1 | -0.83 | Ambiguous | -0.25 | Likely Benign | 0.09 | Likely Benign | 0.284 | Likely Benign | -2.93 | Deleterious | 0.789 | Possibly Damaging | 0.158 | Benign | 3.43 | Benign | 0.07 | Tolerated | 0.1656 | 0.6306 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||
| c.1930G>T | D644Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 D644Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, premPS, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. The remaining tools, FoldX, REVEL, premPS, polyPhen‑2 HumVar, and FATHMM, support a benign effect, while PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default support a pathogenic effect. Overall, the majority of evidence leans 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 | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -10.143 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.03 | Likely Benign | 0.1 | -1.18 | Ambiguous | -0.58 | Ambiguous | -0.04 | Likely Benign | 0.318 | Likely Benign | -4.93 | Deleterious | 0.968 | Probably Damaging | 0.311 | Benign | 3.44 | Benign | 0.02 | Affected | 0.0679 | 0.6094 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1931A>C | D644A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D644A 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, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, Foldetta, and premPS. Only PROVEAN predicts it as pathogenic, while Rosetta and AlphaMissense‑Default are uncertain. 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 benign stability. Based on the aggregate 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. | GAP | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -3.358 | Likely Benign | 0.502 | Ambiguous | Likely Benign | -0.14 | Likely Benign | 0.1 | -0.83 | Ambiguous | -0.49 | Likely Benign | -0.18 | Likely Benign | 0.274 | Likely Benign | -3.90 | Deleterious | 0.311 | Benign | 0.032 | Benign | 3.51 | Benign | 0.39 | Tolerated | 0.3883 | 0.5481 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||
| c.1931A>G | D644G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D644G 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and AlphaMissense‑Default (polyPhen‑2 HumVar is benign). 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‑to‑2 split. Overall, the majority of evidence 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 | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -4.496 | Likely Benign | 0.602 | Likely Pathogenic | Likely Benign | 0.13 | Likely Benign | 0.0 | -0.18 | Likely Benign | -0.03 | Likely Benign | 0.04 | Likely Benign | 0.271 | Likely Benign | -4.38 | Deleterious | 0.456 | Possibly Damaging | 0.069 | Benign | 3.46 | Benign | 0.14 | Tolerated | 0.4035 | 0.5610 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.1931A>T | D644V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D644V 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, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN 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 because it yields a 2‑to‑2 split. Overall, the majority of evidence points to a benign impact. Thus, 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 | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -6.230 | Likely Benign | 0.636 | Likely Pathogenic | Likely Benign | 0.50 | Ambiguous | 0.0 | -0.35 | Likely Benign | 0.08 | Likely Benign | -0.03 | Likely Benign | 0.347 | Likely Benign | -4.96 | Deleterious | 0.198 | Benign | 0.052 | Benign | 3.49 | Benign | 0.11 | Tolerated | 0.0951 | 0.6267 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||
| c.1932C>A | D644E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D644E 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, 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 confirm a benign impact: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective predictions, 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 | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -1.778 | Likely Benign | 0.178 | Likely Benign | Likely Benign | -0.17 | Likely Benign | 0.1 | -0.51 | Ambiguous | -0.34 | Likely Benign | -0.47 | Likely Benign | 0.132 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.55 | Benign | 1.00 | Tolerated | 0.1528 | 0.6186 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1932C>G | D644E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D644E 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, 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 confirm a benign impact: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective predictions, 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 | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -1.778 | Likely Benign | 0.178 | Likely Benign | Likely Benign | -0.17 | Likely Benign | 0.1 | -0.51 | Ambiguous | -0.34 | Likely Benign | -0.47 | Likely Benign | 0.132 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.55 | Benign | 1.00 | Tolerated | 0.1528 | 0.6186 | 3 | 2 | 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 | 0.95 | Ambiguous | 0.4 | 0.61 | Ambiguous | 0.78 | Ambiguous | 0.04 | Likely Benign | 0.360 | Likely Benign | -2.15 | Neutral | 0.031 | Benign | 0.058 | Benign | -1.25 | Pathogenic | 0.32 | Tolerated | 0.1344 | 0.5593 | 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 | 5.82 | Destabilizing | 0.6 | 7.70 | Destabilizing | 6.76 | Destabilizing | 1.13 | Destabilizing | 0.884 | Likely Pathogenic | -4.15 | Deleterious | 0.987 | Probably Damaging | 0.844 | Possibly Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.1940 | 0.4570 | 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 | 0.83 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.23 | Ambiguous | 0.59 | Ambiguous | 0.621 | Likely Pathogenic | -2.18 | Neutral | 0.119 | Benign | 0.468 | Possibly Damaging | -1.35 | Pathogenic | 0.01 | Affected | 0.2410 | 0.4384 | 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 | 4.02 | Destabilizing | 1.6 | 3.09 | Destabilizing | 3.56 | Destabilizing | 1.36 | Destabilizing | 0.915 | Likely Pathogenic | -4.94 | Deleterious | 0.963 | Probably Damaging | 0.844 | Possibly Damaging | -1.40 | Pathogenic | 0.00 | Affected | 0.1610 | 0.1360 | 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 | 1.36 | Ambiguous | 0.2 | 2.33 | Destabilizing | 1.85 | Ambiguous | 1.14 | Destabilizing | 0.804 | Likely Pathogenic | -3.57 | Deleterious | 0.911 | Possibly Damaging | 0.706 | Possibly Damaging | -1.39 | Pathogenic | 0.00 | Affected | 0.2193 | 0.4213 | 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 | 0.52 | Ambiguous | 0.5 | 0.35 | Likely Benign | 0.44 | Likely Benign | -0.25 | Likely Benign | 0.474 | Likely Benign | -3.11 | Deleterious | 0.064 | Benign | 0.048 | Benign | -1.15 | Pathogenic | 0.18 | Tolerated | 0.1333 | 0.5706 | 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 | 0.31 | Likely Benign | 0.2 | -0.05 | Likely Benign | 0.13 | Likely Benign | -1.01 | Stabilizing | 0.338 | Likely Benign | 0.69 | Neutral | 0.016 | Benign | 0.130 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 0.0819 | 0.2461 | 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 | 1.45 | Ambiguous | 0.2 | 0.50 | Ambiguous | 0.98 | Ambiguous | 1.13 | Destabilizing | 0.461 | Likely Benign | -1.00 | Neutral | 0.792 | Possibly Damaging | 0.332 | Benign | -1.36 | Pathogenic | 0.02 | Affected | 0.0999 | 0.2291 | 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 | 4.66 | Destabilizing | 0.7 | 1.38 | Ambiguous | 3.02 | Destabilizing | 0.50 | Likely Benign | 0.692 | Likely Pathogenic | -2.64 | Deleterious | 0.991 | Probably Damaging | 0.854 | Possibly Damaging | -1.14 | Pathogenic | 0.01 | Affected | 0.0552 | 0.1794 | 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 | 3.09 | Destabilizing | 0.1 | 3.00 | Destabilizing | 3.05 | Destabilizing | 2.08 | Destabilizing | 0.925 | Likely Pathogenic | -5.62 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.00 | Affected | 0.0761 | 0.0270 | -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 | 3.08 | Destabilizing | 0.2 | 1.99 | Ambiguous | 2.54 | Destabilizing | 1.95 | Destabilizing | 0.914 | Likely Pathogenic | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.43 | Pathogenic | 0.00 | Affected | 0.0960 | 0.0440 | 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 | 4.00 | Destabilizing | 0.1 | 3.78 | Destabilizing | 3.89 | Destabilizing | 2.34 | Destabilizing | 0.926 | Likely Pathogenic | -4.63 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.44 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.2395 | 0.0858 | -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.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 | 0.56 | Ambiguous | 0.3 | 1.61 | Ambiguous | 1.09 | Ambiguous | 0.55 | Ambiguous | 0.532 | Likely Pathogenic | -0.97 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.42 | Pathogenic | 0.02 | Affected | 0.0674 | 0.1789 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| 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 | 3.42 | Destabilizing | 0.4 | 2.18 | Destabilizing | 2.80 | Destabilizing | 1.12 | Destabilizing | 0.766 | Likely Pathogenic | -5.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.24 | Pathogenic | 0.22 | Tolerated | 0.1473 | 0.1766 | 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 | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | 0.674 | Likely Pathogenic | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 0.1645 | 0.2447 | 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 | 3.54 | Destabilizing | 0.4 | 2.68 | Destabilizing | 3.11 | Destabilizing | 1.13 | Destabilizing | 0.799 | Likely Pathogenic | -6.70 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.21 | Pathogenic | 0.44 | Tolerated | 0.1656 | 0.1583 | -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 | 1.09 | Ambiguous | 0.2 | 1.03 | Ambiguous | 1.06 | Ambiguous | 1.09 | Destabilizing | 0.791 | Likely Pathogenic | -2.92 | Deleterious | 0.988 | Probably Damaging | 0.976 | Probably Damaging | -1.39 | Pathogenic | 0.07 | Tolerated | 0.1046 | 0.1087 | 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 | 4.21 | Destabilizing | 0.4 | 4.43 | Destabilizing | 4.32 | Destabilizing | 2.25 | Destabilizing | 0.917 | Likely Pathogenic | -7.75 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.27 | Pathogenic | 0.10 | Tolerated | 0.3864 | 0.0200 | -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 | 3.92 | Destabilizing | 0.3 | 4.20 | Destabilizing | 4.06 | Destabilizing | 1.64 | Destabilizing | 0.919 | Likely Pathogenic | -7.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.40 | Pathogenic | 0.03 | Affected | 0.2384 | 0.0783 | -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 | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | 0.537 | Likely Pathogenic | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 0.1645 | 0.2447 | 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 | 1.36 | Ambiguous | 0.2 | 1.63 | Ambiguous | 1.50 | Ambiguous | 1.14 | Destabilizing | 0.537 | Likely Pathogenic | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.07 | Pathogenic | 0.19 | Tolerated | 0.1645 | 0.2447 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.745G>A | A249T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249T is listed in ClinVar (ID 1031675.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the balance of evidence favors a benign interpretation, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | Uncertain | 1 | -3.564 | Likely Benign | 0.805 | Likely Pathogenic | Ambiguous | 1.50 | Ambiguous | 0.6 | 1.39 | Ambiguous | 1.45 | Ambiguous | 0.30 | Likely Benign | 0.487 | Likely Benign | -0.96 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.65 | Benign | 0.40 | Tolerated | 3.39 | 15 | 0.0909 | 0.4972 | 1 | 0 | -2.5 | 30.03 | 214.5 | -43.3 | 0.0 | 0.0 | 0.5 | 0.2 | X | Potentially Benign | The methyl group of Ala249, located on the surface of an α helix (res. Ala236-Val250) facing an anti-parallel β sheet strand (res. Ile205-Val209), packs against nearby hydrophobic residues such as Leu200, Leu246, and Val250. In the variant simulations, the hydroxyl group of Thr249, which is not suitable for hydrophobic packing, forms a stable hydrogen bond with the backbone carbonyl of Asn245 in the same helix. Although this interaction could theoretically weaken the structural integrity of the α helix, this destabilizing effect is not observed in the variant simulations. | ||||||||||||||||
| c.745G>C | A249P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249P 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is therefore pathogenic (3 pathogenic vs. 1 benign). High‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates pathogenicity; the SGM‑Consensus (majority vote) is pathogenic; and Foldetta, integrating FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. **Based on the collective 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 | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -10.727 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.76 | Destabilizing | 0.4 | 8.40 | Destabilizing | 5.58 | Destabilizing | 1.04 | Destabilizing | 0.756 | Likely Pathogenic | -3.32 | Deleterious | 0.176 | Benign | 0.039 | Benign | 5.57 | Benign | 0.03 | Affected | 0.1429 | 0.3537 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.745G>T | A249S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. Protein‑stability assessments are mixed: FoldX indicates a benign effect, while Rosetta and Foldetta are uncertain. High‑accuracy predictions show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence—including the high‑accuracy tools—suggests that A249S 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 | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -5.707 | Likely Benign | 0.634 | Likely Pathogenic | Likely Benign | 0.48 | Likely Benign | 0.3 | 0.84 | Ambiguous | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.465 | Likely Benign | -1.40 | Neutral | 0.990 | Probably Damaging | 0.681 | Possibly Damaging | 5.63 | Benign | 0.19 | Tolerated | 0.1962 | 0.3393 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.746C>A | A249E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM. The majority of other in‑silico predictors (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic; FoldX is uncertain and is not counted as evidence for either side. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign 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 | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -13.519 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.60 | Ambiguous | 1.2 | 2.59 | Destabilizing | 2.10 | Destabilizing | 1.02 | Destabilizing | 0.818 | Likely Pathogenic | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.64 | Benign | 0.09 | Tolerated | 0.0799 | 0.1509 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.746C>G | A249G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249G is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for A249G, and this conclusion does not conflict with ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -9.678 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 1.04 | Ambiguous | 0.2 | 2.02 | Destabilizing | 1.53 | Ambiguous | 1.19 | Destabilizing | 0.607 | Likely Pathogenic | -2.97 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.59 | Benign | 0.04 | Affected | 0.1667 | 0.2675 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.746C>T | A249V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A249V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, no high‑accuracy tool provides a definitive pathogenic or benign verdict. Overall, the majority of available predictions (seven pathogenic vs. three benign) lean toward a pathogenic interpretation. 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. | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -9.417 | Likely Pathogenic | 0.856 | Likely Pathogenic | Ambiguous | 1.48 | Ambiguous | 0.6 | 0.51 | Ambiguous | 1.00 | Ambiguous | 0.41 | Likely Benign | 0.652 | Likely Pathogenic | -2.47 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.76 | Benign | 0.03 | Affected | 0.0737 | 0.4677 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| 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 | 0.05 | Likely Benign | 0.1 | 0.03 | Likely Benign | 0.04 | Likely Benign | 0.25 | Likely Benign | 0.268 | Likely Benign | -3.10 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 3.39 | Benign | 0.18 | Tolerated | 0.3353 | 0.1014 | 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 | -0.05 | Likely Benign | 0.1 | -0.21 | Likely Benign | -0.13 | Likely Benign | 0.24 | Likely Benign | 0.324 | Likely Benign | -3.34 | Deleterious | 0.997 | Probably Damaging | 0.966 | Probably Damaging | 3.47 | Benign | 0.16 | Tolerated | 0.2943 | 0.0789 | 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 | 0.30 | Likely Benign | 0.2 | 0.21 | Likely Benign | 0.26 | Likely Benign | 0.22 | Likely Benign | 0.330 | Likely Benign | -5.01 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.43 | Benign | 0.07 | Tolerated | 0.1510 | 0.2859 | 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 | 0.13 | Likely Benign | 0.1 | 0.29 | Likely Benign | 0.21 | Likely Benign | 0.51 | Ambiguous | 0.098 | Likely Benign | -1.42 | Neutral | 0.972 | Probably Damaging | 0.875 | Possibly Damaging | 3.46 | Benign | 0.35 | Tolerated | 3.37 | 29 | 0.3885 | 0.0778 | 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 | 0.16 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.00 | Likely Benign | 0.30 | Likely Benign | 0.350 | Likely Benign | -6.91 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.02 | Affected | 0.0943 | 0.3073 | -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 | 0.37 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.31 | Likely Benign | 0.161 | Likely Benign | -4.05 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.10 | Tolerated | 0.2686 | 0.1314 | 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 | 0.37 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.31 | Likely Benign | 0.161 | Likely Benign | -4.05 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.10 | Tolerated | 0.2686 | 0.1314 | 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 | 0.11 | Likely Benign | 0.1 | 1.24 | Ambiguous | 0.68 | Ambiguous | -0.12 | Likely Benign | 0.265 | Likely Benign | -4.62 | Deleterious | 0.870 | Possibly Damaging | 0.615 | Possibly Damaging | 3.32 | Benign | 0.04 | Affected | 0.1577 | 0.4599 | 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 | 0.15 | Likely Benign | 0.4 | 0.97 | Ambiguous | 0.56 | Ambiguous | -0.14 | Likely Benign | 0.336 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.919 | Probably Damaging | 3.26 | Benign | 0.06 | Tolerated | 0.1804 | 0.5096 | 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 | -0.53 | Ambiguous | 0.2 | 0.72 | Ambiguous | 0.10 | Likely Benign | 0.06 | Likely Benign | 0.363 | Likely Benign | -8.37 | Deleterious | 1.000 | Probably Damaging | 0.965 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0908 | 0.4736 | -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 | -0.18 | Likely Benign | 0.2 | 1.84 | Ambiguous | 0.83 | Ambiguous | 0.09 | Likely Benign | 0.339 | Likely Benign | -7.37 | Deleterious | 0.988 | Probably Damaging | 0.762 | Possibly Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.3758 | 0.4241 | 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 | 0.87 | Ambiguous | 0.2 | 3.20 | Destabilizing | 2.04 | Destabilizing | 0.13 | Likely Benign | 0.368 | Likely Benign | -6.61 | Deleterious | 0.997 | Probably Damaging | 0.933 | Probably Damaging | 3.30 | Benign | 0.07 | Tolerated | 0.3821 | 0.4528 | 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 | 0.07 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.37 | Likely Benign | 0.07 | Likely Benign | 0.381 | Likely Benign | -8.37 | Deleterious | 0.985 | Probably Damaging | 0.895 | Possibly Damaging | 3.27 | Benign | 0.08 | Tolerated | 0.1050 | 0.4604 | -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 | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 0.1766 | 0.4304 | 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 | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 0.1766 | 0.4304 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.898T>A | S300T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300T 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 indicates a pathogenic outcome. 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 view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, 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 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -4.648 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.1 | -0.30 | Likely Benign | 0.28 | Likely Benign | -0.33 | Likely Benign | 0.056 | Likely Benign | 0.50 | Neutral | 0.003 | Benign | 0.002 | Benign | 1.94 | Pathogenic | 0.85 | Tolerated | 0.1409 | 0.6428 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.898T>C | S300P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300P 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 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The remaining tools—FoldX, Foldetta, and ESM1b—return 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, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -7.379 | In-Between | 0.110 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 1.0 | 0.06 | Likely Benign | 0.65 | Ambiguous | 0.50 | Likely Benign | 0.086 | Likely Benign | -2.46 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.54 | Pathogenic | 0.02 | Affected | 0.2192 | 0.5585 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.898T>G | S300A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300A 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign (3 benign vs. 1 pathogenic). Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the 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 | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -5.420 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.08 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.58 | Ambiguous | 0.08 | Likely Benign | 0.031 | Likely Benign | -1.18 | Neutral | 0.139 | Benign | 0.060 | Benign | 1.56 | Pathogenic | 0.20 | Tolerated | 0.5135 | 0.4949 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.899C>A | S300Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300Y has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, premPS, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Two tools (AlphaMissense‑Default and Rosetta) are uncertain and do not influence the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not contradict any ClinVar status (none is available). Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -10.464 | Likely Pathogenic | 0.422 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.4 | 0.55 | Ambiguous | 0.24 | Likely Benign | 0.28 | Likely Benign | 0.116 | Likely Benign | -2.52 | Deleterious | 0.975 | Probably Damaging | 0.686 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | 0.0678 | 0.5395 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.899C>G | S300C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437804‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of reliable predictions indicate a benign impact, 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 | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | 6-33437804-C-G | -6.749 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.2 | 1.45 | Ambiguous | 0.88 | Ambiguous | 0.34 | Likely Benign | 0.129 | Likely Benign | -2.45 | Neutral | 0.975 | Probably Damaging | 0.815 | Possibly Damaging | 1.55 | Pathogenic | 0.01 | Affected | 3.47 | 19 | 0.1005 | 0.6493 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||
| c.899C>T | S300F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S300F 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, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The remaining tool, AlphaMissense‑Default, gives an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions lean toward pathogenicity, while two high‑accuracy methods support a benign effect. Thus, the variant is most likely pathogenic based on the current computational evidence, which does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | Uncertain | 1 | -10.222 | Likely Pathogenic | 0.353 | Ambiguous | Likely Benign | -0.29 | Likely Benign | 0.4 | 0.16 | Likely Benign | -0.07 | Likely Benign | 0.04 | Likely Benign | 0.117 | Likely Benign | -2.66 | Deleterious | 0.975 | Probably Damaging | 0.596 | Possibly Damaging | 1.52 | Pathogenic | 0.01 | Affected | 3.47 | 19 | 0.0579 | 0.5701 | -3 | -2 | 3.6 | 60.10 | 233.6 | -67.6 | -0.1 | 0.0 | 0.4 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl group of the Ser300 side chain, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), hydrogen bonds with the guanidinium group of Arg299 and the backbone amide group and side chain of Ser302. Thus, in the WT simulations, it contributes to the β hairpin stability. In the variant simulations, the phenol ring of Phe300 cannot form any side chain-related hydrogen bonds, and Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | |||||||||||||||
| c.769A>C | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta are uncertain. High‑accuracy methods give the following results: 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 stability outputs, is uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for S257R. This conclusion is not contradicted by 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 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.754 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.769A>G | S257G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257G is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD status: None). Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized. In contrast, a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support this view: AlphaMissense‑Optimized indicates a benign change, whereas the SGM‑Consensus (majority vote) indicates likely pathogenic. The Foldetta stability prediction is unavailable and therefore does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the lack of any ClinVar annotation, the variant is most likely pathogenic, with no contradiction from existing ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.206 | Likely Pathogenic | 0.624 | Likely Pathogenic | Likely Benign | 0.61 | Ambiguous | 0.3 | 0.60 | Ambiguous | 0.61 | Ambiguous | 0.62 | Ambiguous | 0.703 | Likely Pathogenic | -2.95 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 5.79 | Benign | 0.11 | Tolerated | 0.2087 | 0.3589 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.769A>T | S257C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta) and pathogenic predictions (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar). The high‑accuracy consensus methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta—each indicate a benign effect. No folding‑stability assessment is available beyond the benign Foldetta result. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar assertion. Thus, the variant is most likely benign, and this is not contradicted by ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -3.553 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.4 | -0.33 | Likely Benign | 0.09 | Likely Benign | -0.46 | Likely Benign | 0.611 | Likely Pathogenic | 0.02 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 5.76 | Benign | 0.18 | Tolerated | 0.0880 | 0.5151 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.770G>A | S257N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S257N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign calls come from FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and FATHMM, while pathogenic calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments give an inconclusive SGM Consensus (a tie between AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain AlphaMissense‑Optimized result, and a benign Foldetta prediction. No evidence of pathogenicity is supported by the protein‑stability analysis, which indicates a benign effect. Overall, the predictions are mixed, but the majority of high‑accuracy tools lean toward a benign interpretation. This assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -10.508 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.1 | -0.18 | Likely Benign | 0.04 | Likely Benign | 0.85 | Ambiguous | 0.533 | Likely Pathogenic | -2.30 | Neutral | 0.993 | Probably Damaging | 0.968 | Probably Damaging | 5.82 | Benign | 0.16 | Tolerated | 0.0985 | 0.3596 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.770G>C | S257T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257T 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict pathogenic. 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 view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority benign) is 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 S257T 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 | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -8.603 | Likely Pathogenic | 0.243 | Likely Benign | Likely Benign | 0.42 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.13 | Likely Benign | 0.06 | Likely Benign | 0.472 | Likely Benign | -1.58 | Neutral | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 5.83 | Benign | 0.48 | Tolerated | 0.1073 | 0.4898 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.770G>T | S257I 2D AIThe SynGAP1 missense variant S257I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta predicting a benign outcome. FoldX and Rosetta results are uncertain and therefore not considered. Overall, the balance of evidence leans toward a pathogenic interpretation, 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 | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -12.126 | Likely Pathogenic | 0.595 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 1.0 | -1.17 | Ambiguous | -0.20 | Likely Benign | 0.30 | Likely Benign | 0.739 | Likely Pathogenic | -2.97 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.81 | Benign | 0.07 | Tolerated | 0.0681 | 0.5209 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.771C>A | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls come from FoldX, premPS, SIFT, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain outcomes include Rosetta and Foldetta. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta’s stability analysis is inconclusive. Overall, the majority of reliable predictors indicate a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment is consistent with its lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.707 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.771C>G | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R 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, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta and Foldetta are 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 uncertain. Overall, the majority of evaluated tools (7 pathogenic vs. 4 benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this prediction 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 | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.707 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.901G>A | A301T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437806‑G‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. 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, which integrates FoldX‑MD and Rosetta stability calculations, is benign. Overall, the majority of evidence points to a benign effect, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | Uncertain | 5 | 6-33437806-G-A | 2 | 1.24e-6 | -3.448 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.2 | -0.33 | Likely Benign | 0.02 | Likely Benign | 0.03 | Likely Benign | 0.150 | Likely Benign | -0.25 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.15 | Benign | 0.22 | Tolerated | 4.32 | 14 | 0.1362 | 0.7201 | 1 | 0 | -2.5 | 30.03 | 219.8 | -42.8 | -0.1 | 0.0 | -0.5 | 0.2 | Uncertain | The methyl group of Ala301, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), points outward from the β hairpin loop, and its backbone atoms do not participate in the loop formation in the WT simulations. In the variant simulations, the hydroxyl group of the Thr301 side chain also mostly points outward; however, the guanidinium group of Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | ||||||||||||||
| c.901G>C | A301P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301P 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, 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 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 outputs) is benign. Based on the preponderance of evidence, 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. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -3.808 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.47 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.44 | Likely Benign | 0.40 | Likely Benign | 0.225 | Likely Benign | -0.83 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.11 | Benign | 0.06 | Tolerated | 0.1907 | 0.5371 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.901G>T | A301S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy methods corroborate the benign consensus: 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 reports benign. No evidence from these analyses suggests a deleterious effect. Therefore, the variant is most likely benign, 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 Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -2.488 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.1 | -0.32 | Likely Benign | -0.06 | Likely Benign | 0.22 | Likely Benign | 0.151 | Likely Benign | -0.28 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 4.21 | Benign | 0.13 | Tolerated | 0.2706 | 0.6022 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.902C>A | A301D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM all predict benign, whereas polyPhen‑2 (HumDiv and HumVar) and ESM1b predict pathogenic. Tools with uncertain outputs—Rosetta, Foldetta, and AlphaMissense‑Default—do not provide decisive evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized classifies the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign verdict; Foldetta remains inconclusive. Taken together, the preponderance of evidence indicates that A301D is most likely benign, 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 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -10.276 | Likely Pathogenic | 0.488 | Ambiguous | Likely Benign | -0.37 | Likely Benign | 0.2 | -1.15 | Ambiguous | -0.76 | Ambiguous | 0.23 | Likely Benign | 0.224 | Likely Benign | -0.35 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.17 | Benign | 0.07 | Tolerated | 0.1599 | 0.1705 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||
| c.902C>G | A301G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301G 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. 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) also indicates Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies the variant as Benign. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar claim. Therefore, 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 | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -3.085 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.27 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.31 | Likely Benign | 0.37 | Likely Benign | 0.128 | Likely Benign | -0.37 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 4.18 | Benign | 0.28 | Tolerated | 0.2425 | 0.5054 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.902C>T | A301V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301V 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Thus, the overall evidence supports a benign classification for A301V, and this conclusion 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 | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -2.476 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.25 | Likely Benign | 0.1 | 0.48 | Likely Benign | 0.37 | Likely Benign | 0.06 | Likely Benign | 0.116 | Likely Benign | -0.49 | Neutral | 0.997 | Probably Damaging | 0.983 | Probably Damaging | 4.14 | Benign | 0.26 | Tolerated | 0.1096 | 0.6264 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| 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 | 0.25 | Likely Benign | 0.1 | -0.72 | Ambiguous | -0.24 | Likely Benign | -0.65 | Ambiguous | 0.087 | Likely Benign | 0.40 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.51 | Benign | 0.34 | Tolerated | 0.2409 | 0.3416 | 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 | -0.88 | Ambiguous | 0.3 | -1.19 | Ambiguous | -1.04 | Ambiguous | 0.28 | Likely Benign | 0.132 | Likely Benign | -1.49 | Neutral | 0.832 | Possibly Damaging | 0.286 | Benign | 3.40 | Benign | 0.21 | Tolerated | 0.0934 | 0.3197 | -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 | -0.06 | Likely Benign | 0.0 | -0.95 | Ambiguous | -0.51 | Ambiguous | -0.10 | Likely Benign | 0.260 | Likely Benign | -2.94 | Deleterious | 0.977 | Probably Damaging | 0.504 | Possibly Damaging | 3.37 | Benign | 0.16 | Tolerated | 0.1258 | 0.2782 | -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 | -0.19 | Likely Benign | 0.2 | -1.72 | Ambiguous | -0.96 | Ambiguous | 0.32 | Likely Benign | 0.072 | Likely Benign | -0.50 | Neutral | 0.345 | Benign | 0.072 | Benign | 3.63 | Benign | 0.43 | Tolerated | 0.1687 | 0.2090 | 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 | -0.59 | Ambiguous | 0.1 | -1.61 | Ambiguous | -1.10 | Ambiguous | -0.52 | Ambiguous | 0.033 | Likely Benign | -1.04 | Neutral | 0.022 | Benign | 0.011 | Benign | 3.41 | Benign | 0.54 | Tolerated | 0.3539 | 0.3192 | 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 | 0.17 | Likely Benign | 0.2 | -2.19 | Stabilizing | -1.01 | Ambiguous | 0.21 | Likely Benign | 0.099 | Likely Benign | -2.90 | Deleterious | 0.585 | Possibly Damaging | 0.195 | Benign | 3.36 | Benign | 0.12 | Tolerated | 0.1089 | 0.3375 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| 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 | -0.24 | Likely Benign | 0.3 | 0.11 | Likely Benign | -0.07 | Likely Benign | 0.25 | Likely Benign | 0.135 | Likely Benign | -0.82 | Neutral | 0.287 | Benign | 0.038 | Benign | 3.41 | Benign | 0.16 | Tolerated | 0.0694 | 0.3412 | 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 | -0.43 | Likely Benign | 0.0 | 0.59 | Ambiguous | 0.08 | Likely Benign | 0.45 | Likely Benign | 0.135 | Likely Benign | -2.27 | Neutral | 0.165 | Benign | 0.028 | Benign | 3.43 | Benign | 0.11 | Tolerated | 0.0961 | 0.3881 | 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 | -0.26 | Likely Benign | 0.0 | 0.32 | Likely Benign | 0.03 | Likely Benign | 0.54 | Ambiguous | 0.355 | Likely Benign | -4.22 | Deleterious | 0.992 | Probably Damaging | 0.658 | Possibly Damaging | 3.37 | Benign | 0.08 | Tolerated | 0.0670 | 0.3269 | -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 | -0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | -0.01 | Likely Benign | 1.15 | Destabilizing | 0.308 | Likely Benign | -6.07 | Deleterious | 1.000 | Probably Damaging | 0.959 | Probably Damaging | 3.38 | Benign | 0.10 | Tolerated | 0.1232 | 0.0698 | -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 | -0.14 | Likely Benign | 0.0 | 0.33 | Likely Benign | 0.10 | Likely Benign | 0.95 | Ambiguous | 0.053 | Likely Benign | -2.92 | Deleterious | 0.513 | Possibly Damaging | 0.214 | Benign | 3.44 | Benign | 0.93 | Tolerated | 3.37 | 29 | 0.2390 | 0.1800 | 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 | 0.18 | Likely Benign | 0.0 | 1.25 | Ambiguous | 0.72 | Ambiguous | 0.95 | Ambiguous | 0.273 | Likely Benign | -5.88 | Deleterious | 0.841 | Possibly Damaging | 0.997 | Probably Damaging | 3.41 | Benign | 0.24 | Tolerated | 0.1664 | 0.1715 | -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 | 1.34 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.35 | Ambiguous | 1.04 | Destabilizing | 0.382 | Likely Benign | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 3.43 | Benign | 0.07 | Tolerated | 0.4112 | 0.1057 | 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 | 2.99 | Destabilizing | 0.1 | 3.75 | Destabilizing | 3.37 | Destabilizing | 1.10 | Destabilizing | 0.437 | Likely Benign | -3.82 | Deleterious | 0.997 | Probably Damaging | 0.981 | Probably Damaging | 3.40 | Benign | 0.01 | Affected | 0.3486 | 0.0793 | 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 | 2.12 | Destabilizing | 0.1 | 1.17 | Ambiguous | 1.65 | Ambiguous | 0.96 | Ambiguous | 0.442 | Likely Benign | -5.73 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0.1643 | 0.3416 | 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 | -0.12 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.37 | Likely Benign | 0.77 | Ambiguous | 0.213 | Likely Benign | -2.86 | Deleterious | 0.972 | Probably Damaging | 0.926 | Probably Damaging | 3.45 | Benign | 0.12 | Tolerated | 0.4597 | 0.0972 | 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 | 0.39 | Likely Benign | 0.1 | -0.47 | Likely Benign | -0.04 | Likely Benign | 0.33 | Likely Benign | 0.442 | Likely Benign | -5.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.41 | Benign | 0.00 | Affected | 0.0934 | 0.3890 | 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 | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | 0.286 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3282 | 0.1213 | 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 | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | 0.286 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3282 | 0.1213 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| 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 | 0.28 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.21 | Likely Benign | -0.52 | Ambiguous | 0.443 | Likely Benign | 0.22 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | -1.52 | Pathogenic | 0.86 | Tolerated | 0.2952 | 0.0713 | 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 | 0.70 | Ambiguous | 0.0 | 0.31 | Likely Benign | 0.51 | Ambiguous | 0.67 | Ambiguous | 0.536 | Likely Pathogenic | -0.84 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.45 | Pathogenic | 0.21 | Tolerated | 0.2537 | 0.0488 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||
| 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 | 0.82 | Ambiguous | 0.1 | 0.31 | Likely Benign | 0.57 | Ambiguous | 0.78 | Ambiguous | 0.724 | Likely Pathogenic | -2.86 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.55 | Pathogenic | 0.12 | Tolerated | 0.1501 | 0.2451 | 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 | -0.08 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.15 | Likely Benign | 0.36 | Likely Benign | 0.503 | Likely Pathogenic | -0.68 | Neutral | 0.992 | Probably Damaging | 0.980 | Probably Damaging | -1.48 | Pathogenic | 0.27 | Tolerated | 3.37 | 35 | 0.3155 | 0.0579 | 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 | 0.12 | Likely Benign | 0.1 | -0.74 | Ambiguous | -0.31 | Likely Benign | -0.22 | Likely Benign | 0.850 | Likely Pathogenic | -2.39 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.63 | Pathogenic | 0.03 | Affected | 0.0783 | 0.2251 | 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 | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | 0.579 | Likely Pathogenic | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 0.2417 | 0.0764 | 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 | 0.81 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.50 | Ambiguous | 1.06 | Destabilizing | 0.579 | Likely Pathogenic | -1.63 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.57 | Pathogenic | 0.11 | Tolerated | 0.2417 | 0.0764 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.895C>A | R299S 2D 3DClick to see structure in 3D Viewer AISynGAP1 R299S is not reported in ClinVar and is absent from gnomAD. Among in‑silico predictors, benign calls come from REVEL and SIFT, while pathogenic calls are made by FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is inconclusive, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. Overall, the evidence points to a pathogenic 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 | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -7.276 | In-Between | 0.882 | Likely Pathogenic | Ambiguous | 2.86 | Destabilizing | 0.3 | 1.46 | Ambiguous | 2.16 | Destabilizing | 1.07 | Destabilizing | 0.241 | Likely Benign | -3.20 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.07 | Tolerated | 0.2780 | 0.5057 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.895C>G | R299G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized indicates a benign change, but the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. With the majority of evidence pointing to a damaging effect, the variant is most likely pathogenic. 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 | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -8.354 | Likely Pathogenic | 0.629 | Likely Pathogenic | Likely Benign | 3.58 | Destabilizing | 0.2 | 3.16 | Destabilizing | 3.37 | Destabilizing | 1.37 | Destabilizing | 0.248 | Likely Benign | -3.84 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.79 | Pathogenic | 0.02 | Affected | 0.3361 | 0.4150 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.895C>T | R299C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299C is listed in ClinVar with an uncertain significance (ClinVar ID 1335623.0) and is present in gnomAD (ID 6‑33437800‑C‑T). Prediction tools that classify the variant as benign include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also uncertain. Overall, the balance of evidence favors a pathogenic interpretation, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of disease relevance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | Conflicting | 2 | 6-33437800-C-T | 3 | 1.86e-6 | -6.326 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 1.85 | Ambiguous | 0.4 | 0.61 | Ambiguous | 1.23 | Ambiguous | 0.76 | Ambiguous | 0.344 | Likely Benign | -3.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.65 | Pathogenic | 0.06 | Tolerated | 3.39 | 19 | 0.3035 | 0.4564 | -4 | -3 | 7.0 | -53.05 | 210.7 | 91.3 | 0.1 | 0.0 | 0.0 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the thiol group of the Cys299 side chain is unable to form any of these well-coordinated or strong interactions, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association. | ||||||||||||
| c.896G>A | R299H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299H is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437801‑G‑A). Functional prediction tools cluster into two groups: benign predictions from REVEL and AlphaMissense‑Optimized, and pathogenic predictions from FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; Rosetta, ESM1b, and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a tie between pathogenic and uncertain calls. Overall, the majority of evidence points to a pathogenic effect, which is consistent with the ClinVar uncertain designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | Conflicting | 2 | 6-33437801-G-A | 10 | 6.20e-6 | -7.731 | In-Between | 0.388 | Ambiguous | Likely Benign | 3.97 | Destabilizing | 1.0 | 0.94 | Ambiguous | 2.46 | Destabilizing | 1.41 | Destabilizing | 0.238 | Likely Benign | -3.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 3.39 | 19 | 0.3293 | 0.2982 | 2 | 0 | 1.3 | -19.05 | 211.2 | 72.5 | -0.1 | 0.2 | -0.2 | 0.3 | X | Potentially Pathogenic | The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the imidazole ring of His299 (epsilon protonated state) hydrogen bonds with the carbonyl group of Asp304 and the hydroxyl group of Ser300. However, it does not form as many or as strong interactions as arginine, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant.Additionally, His299 prefers to hydrophobically interact with other hydrophobic residues inside the C2 domain core (e.g., Val306, Leu274), which destabilizes the C2 domain. Indeed, the β strand partially unfolds during the second simulation. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association. | ||||||||||||||
| c.896G>C | R299P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299P is not reported in ClinVar or gnomAD, indicating no publicly available frequency data. Prediction tools cluster into benign and pathogenic groups: benign predictions include REVEL and AlphaMissense‑Optimized, while pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, SIFT, FATHMM, and AlphaMissense‑Default; ESM1b is uncertain. The SGM‑Consensus label is Likely Pathogenic. High‑accuracy tools give a clear signal: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta also predicts pathogenic. Overall, the predictions strongly favor a pathogenic interpretation, with no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -7.662 | In-Between | 0.722 | Likely Pathogenic | Likely Benign | 4.10 | Destabilizing | 0.2 | 3.01 | Destabilizing | 3.56 | Destabilizing | 1.19 | Destabilizing | 0.295 | Likely Benign | -4.09 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.68 | Pathogenic | 0.02 | Affected | 0.2072 | 0.5379 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.896G>T | R299L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R299L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Stability‑based methods FoldX, Rosetta, Foldetta, and premPS returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of consensus predictions favor a pathogenic effect, and the high‑accuracy tools do not overturn this trend. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for R299L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -5.171 | Likely Benign | 0.645 | Likely Pathogenic | Likely Benign | 1.37 | Ambiguous | 0.6 | 0.77 | Ambiguous | 1.07 | Ambiguous | 0.59 | Ambiguous | 0.356 | Likely Benign | -4.03 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.02 | Affected | 0.2027 | 0.5202 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.904T>A | S302T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302T is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates 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. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -4.742 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.1 | 0.10 | Likely Benign | 0.15 | Likely Benign | -0.08 | Likely Benign | 0.043 | Likely Benign | -0.55 | Neutral | 0.037 | Benign | 0.042 | Benign | 4.16 | Benign | 0.15 | Tolerated | 0.1715 | 0.6886 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.904T>C | S302P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302P is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only Rosetta predicts a pathogenic outcome, while FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also supports a benign classification. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence points to a benign impact for S302P, 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 | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -2.485 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 1.19 | Ambiguous | 0.4 | 2.74 | Destabilizing | 1.97 | Ambiguous | 0.14 | Likely Benign | 0.101 | Likely Benign | -0.89 | Neutral | 0.157 | Benign | 0.153 | Benign | 4.11 | Benign | 0.20 | Tolerated | 0.2522 | 0.6243 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.904T>G | S302A 2D AIThe SynGAP1 missense variant S302A 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 Foldetta. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -2.583 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.4 | 0.65 | Ambiguous | 0.43 | Likely Benign | 0.02 | Likely Benign | 0.044 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.16 | Benign | 0.20 | Tolerated | 0.5358 | 0.5407 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.905C>A | S302Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302Y 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, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SIFT, polyPhen‑2 HumDiv, and ESM1b. Two tools give uncertain results: AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, 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. | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -9.674 | Likely Pathogenic | 0.355 | Ambiguous | Likely Benign | -0.02 | Likely Benign | 0.1 | 0.56 | Ambiguous | 0.27 | Likely Benign | -0.17 | Likely Benign | 0.070 | Likely Benign | -1.03 | Neutral | 0.801 | Possibly Damaging | 0.383 | Benign | 4.07 | Benign | 0.01 | Affected | 0.0882 | 0.5990 | -3 | -2 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||
| c.905C>G | S302C 2D AIThe SynGAP1 missense variant S302C 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, premPS, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain predictions come from Rosetta, Foldetta, and ESM1b. 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 for S302C, 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 Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -7.290 | In-Between | 0.105 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.5 | 1.24 | Ambiguous | 0.78 | Ambiguous | -0.04 | Likely Benign | 0.070 | Likely Benign | -0.83 | Neutral | 0.833 | Possibly Damaging | 0.455 | Possibly Damaging | 4.05 | Benign | 0.02 | Affected | 0.1221 | 0.6514 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.905C>T | S302F 2D AIThe SynGAP1 missense variant S302F 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and ESM1b; Rosetta’s output is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence supports a benign impact for S302F, 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 | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -9.483 | Likely Pathogenic | 0.321 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.5 | 0.71 | Ambiguous | 0.34 | Likely Benign | -0.21 | Likely Benign | 0.073 | Likely Benign | -0.92 | Neutral | 0.570 | Possibly Damaging | 0.383 | Benign | 4.06 | Benign | 0.01 | Affected | 0.0705 | 0.6092 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.742C>G | R248G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248G 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 predictors—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 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 predicts pathogenic. No prediction or folding stability 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 status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | -13.413 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.23 | Destabilizing | 0.7 | 2.67 | Destabilizing | 2.45 | Destabilizing | 1.33 | Destabilizing | 0.770 | Likely Pathogenic | -6.07 | Deleterious | 0.958 | Probably Damaging | 0.502 | Possibly Damaging | 5.70 | Benign | 0.00 | Affected | 0.3011 | 0.3385 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.742C>T | R248W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248W 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 Rosetta, Foldetta, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results from FoldX and premPS are treated as unavailable. 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) as benign. 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 | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | Uncertain | 1 | -11.647 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.3 | -0.20 | Likely Benign | 0.49 | Likely Benign | 0.89 | Ambiguous | 0.699 | Likely Pathogenic | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.948 | Probably Damaging | 5.62 | Benign | 0.00 | Affected | 3.41 | 14 | 0.1124 | 0.4037 | 2 | -3 | 3.6 | 30.03 | 266.4 | 42.3 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg248, located on an α helix (res. Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the indole group of Trp248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Instead, in the variant simulations, the indole ring of Trp248 stacks against Pro252, which makes a turn after the α helix. | ||||||||||||||||
| c.743G>A | R248Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248Q is catalogued in gnomAD (ID 6‑33435594‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: benign predictions come from FoldX and FATHMM, whereas pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by 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 R248Q, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | 6-33435594-G-A | 2 | 1.24e-6 | -10.573 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.45 | Likely Benign | 0.2 | 1.67 | Ambiguous | 1.06 | Ambiguous | 1.05 | Destabilizing | 0.739 | Likely Pathogenic | -3.34 | Deleterious | 0.999 | Probably Damaging | 0.715 | Possibly Damaging | 5.74 | Benign | 0.01 | Affected | 3.41 | 14 | 0.2572 | 0.2549 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||
| c.743G>C | R248P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248P is listed in ClinVar as Pathogenic (ClinVar ID 1065478.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (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 pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming consensus of pathogenic predictions and the high‑accuracy tool results, 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 | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | Likely Pathogenic | 1 | -10.751 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.09 | Destabilizing | 0.6 | 8.87 | Destabilizing | 5.98 | Destabilizing | 1.21 | Destabilizing | 0.848 | Likely Pathogenic | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.878 | Possibly Damaging | 5.64 | Benign | 0.00 | Affected | 3.41 | 14 | 0.1943 | 0.4528 | 0 | -2 | 2.9 | -59.07 | 223.8 | 126.6 | 0.0 | 0.0 | -0.2 | 0.1 | X | X | Potentially Pathogenic | The guanidinium group of Arg248, located on an α helix (residues Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Additionally, Pro248 lacks a free amide group needed for hydrogen bonding with the backbone carbonyl group of Asn245, disrupting the continuity of the α helix. | |||||||||||||||
| c.743G>T | R248L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta and FATHMM, whereas the majority of algorithms predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled uncertain are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the consensus of the available evidence points to a pathogenic effect for R248L, 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 | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | -12.110 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.13 | Ambiguous | 0.5 | 0.01 | Likely Benign | 0.57 | Ambiguous | 0.67 | Ambiguous | 0.825 | Likely Pathogenic | -6.06 | Deleterious | 0.979 | Probably Damaging | 0.680 | Possibly Damaging | 5.66 | Benign | 0.03 | Affected | 0.1616 | 0.4741 | -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 | 1.12 | Ambiguous | 0.1 | 0.83 | Ambiguous | 0.98 | Ambiguous | 0.00 | Likely Benign | 0.140 | Likely Benign | -2.48 | Neutral | 0.835 | Possibly Damaging | 0.217 | Benign | 3.40 | Benign | 0.19 | Tolerated | 0.0935 | 0.3270 | 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 | -0.62 | Ambiguous | 0.0 | -0.41 | Likely Benign | -0.52 | Ambiguous | 0.47 | Likely Benign | 0.074 | Likely Benign | -1.71 | Neutral | 0.229 | Benign | 0.045 | Benign | 3.43 | Benign | 0.43 | Tolerated | 0.1544 | 0.2025 | 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 | 0.81 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.03 | Ambiguous | 0.20 | Likely Benign | 0.135 | Likely Benign | -3.81 | Deleterious | 0.931 | Possibly Damaging | 0.230 | Benign | 3.43 | Benign | 0.07 | Tolerated | 0.0535 | 0.3624 | -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 | 0.58 | Ambiguous | 0.0 | 0.16 | Likely Benign | 0.37 | Likely Benign | 0.11 | Likely Benign | 0.079 | Likely Benign | -1.27 | Neutral | 0.007 | Benign | 0.005 | Benign | 3.48 | Benign | 0.14 | Tolerated | 0.0969 | 0.3341 | 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 | 0.52 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.30 | Likely Benign | -0.50 | Ambiguous | 0.104 | Likely Benign | 1.15 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.53 | Benign | 0.92 | Tolerated | 0.2024 | 0.3556 | 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 | 0.97 | Ambiguous | 0.9 | 1.10 | Ambiguous | 1.04 | Ambiguous | 0.10 | Likely Benign | 0.100 | Likely Benign | -4.07 | Deleterious | 0.322 | Benign | 0.109 | Benign | 3.47 | Benign | 0.03 | Affected | 0.0554 | 0.3772 | -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 | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | 0.058 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 0.1660 | 0.2550 | 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 | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | 0.057 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 0.1660 | 0.2550 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.892C>A | P298T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298T 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, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain results and are treated as unavailable for pathogenicity inference. 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. Overall, the preponderance of evidence points to a benign effect for P298T, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -7.366 | In-Between | 0.104 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.2 | 1.03 | Ambiguous | 1.24 | Ambiguous | 0.04 | Likely Benign | 0.209 | Likely Benign | -0.13 | Neutral | 0.939 | Possibly Damaging | 0.739 | Possibly Damaging | 1.96 | Pathogenic | 1.00 | Tolerated | 0.1595 | 0.6349 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.892C>G | P298A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298A 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, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Based on the preponderance of benign predictions and the lack of pathogenic consensus, 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 | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -6.082 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 1.22 | Ambiguous | 0.1 | 1.17 | Ambiguous | 1.20 | Ambiguous | 0.50 | Likely Benign | 0.191 | Likely Benign | -0.98 | Neutral | 0.885 | Possibly Damaging | 0.589 | Possibly Damaging | 1.94 | Pathogenic | 0.66 | Tolerated | 0.3761 | 0.5787 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.892C>T | P298S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298S is listed in ClinVar as Benign (ClinVar ID 2965590.0) and is present in gnomAD (ID 6‑33437797‑C‑T). Prediction tools that agree on a benign effect include REVEL, 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. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. No evidence from FoldX, Rosetta, or premPS is available to support either outcome. Overall, the majority of predictions support a benign impact, aligning with the ClinVar designation. Thus, the variant is most likely benign and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | Benign | 1 | 6-33437797-C-T | 5 | 3.10e-6 | -6.342 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 1.38 | Ambiguous | 0.2 | 1.41 | Ambiguous | 1.40 | Ambiguous | 0.58 | Ambiguous | 0.189 | Likely Benign | -1.20 | Neutral | 0.991 | Probably Damaging | 0.898 | Possibly Damaging | 2.03 | Pathogenic | 0.85 | Tolerated | 3.39 | 20 | 0.3678 | 0.5855 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||
| c.893C>A | P298H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P298H 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, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Remaining tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta, premPS) 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 is uncertain. Overall, the majority of predictions (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic interpretation. Therefore, the variant is most likely pathogenic, 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. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -9.777 | Likely Pathogenic | 0.443 | Ambiguous | Likely Benign | 1.57 | Ambiguous | 0.2 | 1.49 | Ambiguous | 1.53 | Ambiguous | 0.83 | Ambiguous | 0.313 | Likely Benign | -2.37 | Neutral | 0.999 | Probably Damaging | 0.964 | Probably Damaging | 1.92 | Pathogenic | 0.04 | Affected | 0.1769 | 0.4943 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||
| c.893C>G | P298R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298R has no ClinVar entry and is not reported in gnomAD. Computational predictors fall into two consensus groups: benign predictions come from REVEL, FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported only by Foldetta and premPS. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta reports an uncertain stability change. Overall, the majority of evidence points toward a pathogenic effect, and this assessment is not contradicted by ClinVar, 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 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -11.427 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 0.45 | Likely Benign | 0.0 | 2.08 | Destabilizing | 1.27 | Ambiguous | 0.61 | Ambiguous | 0.280 | Likely Benign | -1.83 | Neutral | 0.997 | Probably Damaging | 0.952 | Probably Damaging | 2.03 | Pathogenic | 0.09 | Tolerated | 0.1299 | 0.3872 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.893C>T | P298L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P298L 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, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive 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 outcome; and Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -7.334 | In-Between | 0.107 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.2 | 1.53 | Ambiguous | 1.07 | Ambiguous | -0.16 | Likely Benign | 0.267 | Likely Benign | -0.82 | Neutral | 0.885 | Possibly Damaging | 0.589 | Possibly Damaging | 1.91 | Pathogenic | 0.21 | Tolerated | 0.2137 | 0.6795 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.1963C>A | L655M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655M is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the change 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 indicates “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the unanimous benign predictions and the absence of any pathogenic calls, the variant is most likely benign, 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 Benign | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | -3.077 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.23 | Likely Benign | -0.22 | Likely Benign | 0.076 | Likely Benign | 0.58 | Neutral | 0.048 | Benign | 0.037 | Benign | 3.43 | Benign | 0.18 | Tolerated | 0.0979 | 0.3252 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1963C>G | L655V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655V 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. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. No tools predict pathogenicity, and the uncertain stability assessment does not alter the overall benign inference. Therefore, based on the available predictions, 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 | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | -6.743 | Likely Benign | 0.127 | Likely Benign | Likely Benign | 0.78 | Ambiguous | 0.0 | 0.58 | Ambiguous | 0.68 | Ambiguous | 0.38 | Likely Benign | 0.058 | Likely Benign | -0.62 | Neutral | 0.008 | Benign | 0.003 | Benign | 3.45 | Benign | 0.44 | Tolerated | 0.1551 | 0.3190 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1964T>A | L655Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655Q 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, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity, while Rosetta remains inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign impact for L655Q, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | Uncertain | 1 | -5.278 | Likely Benign | 0.144 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.0 | 0.69 | Ambiguous | 0.34 | Likely Benign | -0.15 | Likely Benign | 0.139 | Likely Benign | 0.61 | Neutral | 0.955 | Possibly Damaging | 0.602 | Possibly Damaging | 3.59 | Benign | 0.65 | Tolerated | 3.39 | 24 | 0.1248 | 0.0972 | -2 | -2 | -7.3 | 14.97 | 229.9 | -8.6 | 0.0 | 0.0 | 0.4 | 0.0 | X | Potentially Benign | The iso-butyl side chain of Leu655, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Gln655 dynamically interacts with neighboring residues (e.g., Glu651, Glu656, Arg544) on the protein surface, with no negative structural effects. | ||||||||||||||||
| c.1964T>C | L655P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L655P is catalogued in gnomAD (ID 6‑33441223‑T‑C) but has no ClinVar entry. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, SIFT, and FATHMM, whereas pathogenic calls are made by Rosetta, Foldetta, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are uncertain. High‑accuracy assessments give AlphaMissense‑Optimized as pathogenic, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Overall, the majority of evidence points to a pathogenic effect. 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. | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | 6-33441223-T-C | 1 | 6.20e-7 | -9.771 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.33 | Ambiguous | 0.5 | 6.52 | Destabilizing | 3.93 | Destabilizing | 0.57 | Ambiguous | 0.126 | Likely Benign | -1.36 | Neutral | 0.981 | Probably Damaging | 0.772 | Possibly Damaging | 3.47 | Benign | 0.32 | Tolerated | 3.39 | 24 | 0.3598 | 0.1274 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| c.1964T>G | L655R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, and the majority of consensus methods (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all score the variant as benign. The only inconclusive result comes from Rosetta, which is treated as unavailable. High‑accuracy assessments reinforce this benign prediction: 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 predicts benign. Thus, based on the available predictions, the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | -4.848 | Likely Benign | 0.284 | Likely Benign | Likely Benign | -0.40 | Likely Benign | 0.0 | 0.54 | Ambiguous | 0.07 | Likely Benign | -0.09 | Likely Benign | 0.160 | Likely Benign | 0.46 | Neutral | 0.006 | Benign | 0.001 | Benign | 3.50 | Benign | 0.60 | Tolerated | 0.1589 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| 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 | 0.02 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.02 | Likely Benign | 0.46 | Likely Benign | 0.524 | Likely Pathogenic | -3.82 | Deleterious | 0.991 | Probably Damaging | 0.951 | Probably Damaging | 3.35 | Benign | 0.02 | Affected | 0.1784 | 0.5311 | 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 | -0.03 | Likely Benign | 0.0 | 0.20 | Likely Benign | 0.09 | Likely Benign | 0.70 | Ambiguous | 0.240 | Likely Benign | -2.86 | Deleterious | 0.987 | Probably Damaging | 0.946 | Probably Damaging | 3.40 | Benign | 0.12 | Tolerated | 3.38 | 31 | 0.0787 | 0.5018 | 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 | 0.09 | Likely Benign | 0.0 | -0.34 | Likely Benign | -0.13 | Likely Benign | 0.56 | Ambiguous | 0.476 | Likely Benign | -5.73 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | 0.2846 | 0.4876 | 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 | 0.80 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.80 | Ambiguous | 0.69 | Ambiguous | 0.523 | Likely Pathogenic | -6.68 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.2446 | 0.4202 | 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 | 0.34 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.17 | Likely Benign | 0.32 | Likely Benign | 0.572 | Likely Pathogenic | -6.68 | Deleterious | 0.992 | Probably Damaging | 0.967 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | 0.0414 | 0.5233 | -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 | 0.81 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.65 | Ambiguous | 0.91 | Ambiguous | 0.136 | Likely Benign | -2.86 | Deleterious | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.54 | Benign | 0.09 | Tolerated | 3.38 | 31 | 0.1437 | 0.3526 | 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 | 0.81 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.65 | Ambiguous | 0.91 | Ambiguous | 0.136 | Likely Benign | -2.86 | Deleterious | 0.977 | Probably Damaging | 0.921 | Probably Damaging | 3.54 | Benign | 0.09 | Tolerated | 3.38 | 31 | 0.1437 | 0.3526 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.907G>A | G303R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G303R is catalogued in gnomAD (6-33437812-G-A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome; the remaining tools (FoldX, Foldetta, premPS, ESM1b) are inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, while Foldetta remains uncertain. Taken together, the majority of evidence points to a benign 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. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | 6-33437812-G-A | 1 | 6.20e-7 | -7.493 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 1.44 | Ambiguous | 0.4 | 0.23 | Likely Benign | 0.84 | Ambiguous | 0.73 | Ambiguous | 0.048 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.99 | Benign | 0.06 | Tolerated | 3.55 | 18 | 0.0839 | 0.4490 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.907G>C | G303R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303R 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The remaining tools—FoldX, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, 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. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -7.493 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 1.44 | Ambiguous | 0.4 | 0.23 | Likely Benign | 0.84 | Ambiguous | 0.73 | Ambiguous | 0.048 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.99 | Benign | 0.06 | Tolerated | 3.55 | 18 | 0.0839 | 0.4490 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
| c.907G>T | G303W 2D 3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G303W variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are 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, PROVEAN) is inconclusive, and Foldetta’s stability prediction is also unavailable. Overall, the evidence is evenly split between benign and pathogenic predictions, providing no clear bias toward either outcome. This balanced prediction does not contradict ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -9.041 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 1.69 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.40 | Ambiguous | 0.28 | Likely Benign | 0.157 | Likely Benign | -1.63 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.0663 | 0.4553 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.908G>A | G303E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303E is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437813‑G‑A). Across the available in‑silico predictors, benign calls are made by REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls are made by SIFT and ESM1b; the remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation, as no pathogenic classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | 6-33437813-G-A | 3 | 1.86e-6 | -9.339 | Likely Pathogenic | 0.549 | Ambiguous | Likely Benign | 1.87 | Ambiguous | 0.5 | 0.37 | Likely Benign | 1.12 | Ambiguous | 0.89 | Ambiguous | 0.063 | Likely Benign | -1.56 | Neutral | 0.001 | Benign | 0.005 | Benign | 4.04 | Benign | 0.05 | Affected | 3.55 | 18 | 0.1155 | 0.4172 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||
| c.908G>C | G303A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis is uncertain. Overall, the variant is most likely benign based on the consensus of predictive tools, 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 Benign | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -1.965 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 1.66 | Ambiguous | 0.2 | -0.51 | Ambiguous | 0.58 | Ambiguous | 0.10 | Likely Benign | 0.034 | Likely Benign | -0.90 | Neutral | 0.112 | Benign | 0.058 | Benign | 4.07 | Benign | 0.35 | Tolerated | 0.3724 | 0.5325 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.908G>T | G303V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all indicate a tolerated change. Pathogenic signals arise only from SIFT and FoldX, while Rosetta and Foldetta are inconclusive. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields Likely Benign, and Foldetta remains uncertain. Overall, the preponderance of evidence points to 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 | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -3.046 | Likely Benign | 0.198 | Likely Benign | Likely Benign | 3.06 | Destabilizing | 0.6 | -0.72 | Ambiguous | 1.17 | Ambiguous | 0.14 | Likely Benign | 0.071 | Likely Benign | -1.57 | Neutral | 0.011 | Benign | 0.017 | Benign | 3.96 | Benign | 0.01 | Affected | 0.1002 | 0.4577 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.2071A>C | T691P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691P is listed in ClinVar (ID 648126.0) as Pathogenic and is not reported in gnomAD. Across the broad panel of in‑silico predictors, three tools (REVEL, SIFT, FATHMM) classify the change as benign, whereas the remaining 11 predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score) report it as pathogenic. High‑accuracy assessments further support a deleterious effect: the AlphaMissense‑Optimized model is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and the Foldetta stability analysis (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the preponderance of evidence indicates that T691P is most likely pathogenic, which is consistent with its ClinVar classification and does not contradict the database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | Likely Pathogenic | 1 | -13.801 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 5.04 | Destabilizing | 0.4 | 6.09 | Destabilizing | 5.57 | Destabilizing | 1.27 | Destabilizing | 0.214 | Likely Benign | -3.43 | Deleterious | 1.000 | Probably Damaging | 0.952 | Probably Damaging | 3.43 | Benign | 0.06 | Tolerated | 3.43 | 14 | 0.1466 | 0.4236 | 0 | -1 | -0.9 | -3.99 | 188.9 | 33.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | X | Potentially Pathogenic | The hydroxyl side chain of Thr691, located in an α-helix (res. Leu696-Leu685), can form hydrogen bonds with the backbone carbonyl and the side chain guanidinium group of Arg687. This interaction facilitates the simultaneous formation of salt bridges between Arg687 and Glu688 on the same α-helix. Additionally, Thr691 occasionally interacts with the thioether side chain of Met409 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399), although this interaction is not consistently maintained throughout the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro691 lacks hydrogen bond donors, making a similar setup impossible. Moreover, proline lacks a free amide group necessary for hydrogen bonding with the carbonyl group of Arg687, introducing a slight bend in the α-helix and compromising its integrity. | |||||||||||||||
| c.2071A>G | T691A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or tolerated. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while premPS and ESM1b are uncertain. The SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No prediction contradicts the ClinVar status, which is currently unreported. Based on the preponderance of evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | -7.840 | In-Between | 0.086 | Likely Benign | Likely Benign | -0.11 | Likely Benign | 0.0 | 0.22 | Likely Benign | 0.06 | Likely Benign | 0.69 | Ambiguous | 0.063 | Likely Benign | -1.84 | Neutral | 0.751 | Possibly Damaging | 0.131 | Benign | 3.49 | Benign | 0.33 | Tolerated | 0.2819 | 0.3251 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.2071A>T | T691S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; premPS is uncertain. 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. Based on the overall consensus of the available 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 | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | -9.274 | Likely Pathogenic | 0.123 | Likely Benign | Likely Benign | 0.44 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.34 | Likely Benign | 0.88 | Ambiguous | 0.041 | Likely Benign | -1.67 | Neutral | 0.860 | Possibly Damaging | 0.584 | Possibly Damaging | 3.49 | Benign | 0.61 | Tolerated | 0.2213 | 0.3343 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.2072C>A | T691K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 T691K missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, Rosetta, Foldetta, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX returned an uncertain result and is not counted. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus indicates pathogenic. Overall, the majority of tools and the consensus high‑accuracy prediction lean toward pathogenicity. Thus, 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 | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | -12.104 | Likely Pathogenic | 0.715 | Likely Pathogenic | Likely Benign | -0.50 | Ambiguous | 0.1 | -0.31 | Likely Benign | -0.41 | Likely Benign | 1.27 | Destabilizing | 0.147 | Likely Benign | -3.20 | Deleterious | 0.937 | Possibly Damaging | 0.120 | Benign | 3.42 | Benign | 0.04 | Affected | 0.0851 | 0.2628 | 0 | -1 | -3.2 | 27.07 | |||||||||||||||||||||||||||||
| c.2072C>G | T691R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by 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, labels 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. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | -12.228 | Likely Pathogenic | 0.621 | Likely Pathogenic | Likely Benign | -1.27 | Ambiguous | 0.3 | -0.94 | Ambiguous | -1.11 | Ambiguous | 1.35 | Destabilizing | 0.180 | Likely Benign | -3.66 | Deleterious | 0.993 | Probably Damaging | 0.566 | Possibly Damaging | 3.48 | Benign | 0.02 | Affected | 0.0729 | 0.2478 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||
| c.2072C>T | T691I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691I is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33441331‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Foldetta, and premPS. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Overall, the evidence overwhelmingly indicates that T691I is most likely benign, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | 6-33441331-C-T | 1 | 6.20e-7 | -5.857 | Likely Benign | 0.202 | Likely Benign | Likely Benign | -1.08 | Ambiguous | 0.1 | -2.12 | Stabilizing | -1.60 | Ambiguous | -0.61 | Ambiguous | 0.052 | Likely Benign | -1.19 | Neutral | 0.040 | Benign | 0.003 | Benign | 3.49 | Benign | 0.34 | Tolerated | 3.43 | 14 | 0.0644 | 0.5397 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| c.889A>C | K297Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K297Q missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, Rosetta, and Foldetta. In contrast, the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX is uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as benign. Overall, the preponderance of evidence points to a pathogenic effect for K297Q. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -8.393 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.66 | Ambiguous | 0.3 | 0.14 | Likely Benign | 0.40 | Likely Benign | 1.06 | Destabilizing | 0.450 | Likely Benign | -3.48 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.65 | Pathogenic | 0.01 | Affected | 0.4768 | 0.1738 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.889A>G | K297E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; the only inconclusive result is FoldX, which is listed as “Uncertain” and is treated as unavailable. 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. Based on the collective predictions, K297E 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 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -10.143 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.99 | Ambiguous | 0.4 | 2.43 | Destabilizing | 2.21 | Destabilizing | 1.16 | Destabilizing | 0.507 | Likely Pathogenic | -3.54 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.61 | Pathogenic | 0.02 | Affected | 0.4073 | 0.1547 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.890A>C | K297T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K297T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are none, whereas those that predict a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods specifically show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic 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 Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -10.110 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.1 | 1.19 | Ambiguous | 1.37 | Ambiguous | 0.59 | Ambiguous | 0.551 | Likely Pathogenic | -5.28 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.62 | Pathogenic | 0.01 | Affected | 0.2294 | 0.4024 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.890A>G | K297R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297R 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, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, and ESM1b. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign; and Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, predicts benign. Based on the aggregate of these predictions, 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. | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -7.877 | In-Between | 0.314 | Likely Benign | Likely Benign | -0.86 | Ambiguous | 0.3 | 0.67 | Ambiguous | -0.10 | Likely Benign | 0.66 | Ambiguous | 0.257 | Likely Benign | -2.36 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.66 | Pathogenic | 0.19 | Tolerated | 0.4828 | 0.1506 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.890A>T | K297M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297M is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports Likely Pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a Benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) points to the variant being most likely pathogenic, 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 | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -11.472 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.09 | Likely Benign | 0.1 | 0.32 | Likely Benign | 0.21 | Likely Benign | 0.49 | Likely Benign | 0.538 | Likely Pathogenic | -5.20 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.61 | Pathogenic | 0.00 | Affected | 0.1438 | 0.4394 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.891G>C | K297N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. 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. Based on the preponderance of pathogenic predictions and the lack of benign consensus, 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 | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -11.328 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.1 | 1.60 | Ambiguous | 1.34 | Ambiguous | 1.15 | Destabilizing | 0.253 | Likely Benign | -4.31 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.61 | Pathogenic | 0.01 | Affected | 0.3797 | 0.2265 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.891G>T | K297N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. 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. Based on the preponderance of pathogenic predictions and the lack of benign consensus, K297N 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 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -11.328 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.1 | 1.60 | Ambiguous | 1.34 | Ambiguous | 1.15 | Destabilizing | 0.253 | Likely Benign | -4.31 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.61 | Pathogenic | 0.01 | Affected | 0.3797 | 0.2265 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1933T>A | F645I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F645I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are given by premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) report uncertain or inconclusive outcomes. High‑accuracy assessments indicate that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is uncertain. Overall, the majority of evaluated predictors (five pathogenic vs four benign) lean toward a pathogenic effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for F645I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -13.055 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 1.12 | Ambiguous | 0.2 | 1.68 | Ambiguous | 1.40 | Ambiguous | 1.01 | Destabilizing | 0.299 | Likely Benign | -4.24 | Deleterious | 0.190 | Benign | 0.019 | Benign | 3.44 | Benign | 0.04 | Affected | 0.1920 | 0.2891 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1933T>C | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this view. Overall, the majority of computational evidence points to a pathogenic impact for F645L, 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.264 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1933T>G | F645V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F645V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect are premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessments give an uncertain result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). No definitive folding‑stability change is reported. Overall, the majority of evidence points to a pathogenic impact for F645V, 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. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -12.175 | Likely Pathogenic | 0.810 | Likely Pathogenic | Ambiguous | 1.98 | Ambiguous | 0.1 | 1.70 | Ambiguous | 1.84 | Ambiguous | 1.02 | Destabilizing | 0.316 | Likely Benign | -4.41 | Deleterious | 0.036 | Benign | 0.018 | Benign | 3.40 | Benign | 0.02 | Affected | 0.2163 | 0.2919 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1934T>A | F645Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645Y 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, Rosetta, 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). Tools with inconclusive results are FoldX (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized predicting Benign, the SGM‑Consensus indicating Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicting Benign. No tool predicts pathogenicity. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as the variant is not currently classified in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -3.544 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.2 | 0.21 | Likely Benign | 0.37 | Likely Benign | -0.61 | Ambiguous | 0.141 | Likely Benign | 2.40 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.61 | Benign | 1.00 | Tolerated | 0.1506 | 0.2189 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1934T>C | F645S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F645S 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, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while both the SGM Consensus and Foldetta predict pathogenicity. No evidence from ClinVar contradicts these findings. Overall, the preponderance of predictions supports a pathogenic classification for F645S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -9.748 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 2.49 | Destabilizing | 0.2 | 2.30 | Destabilizing | 2.40 | Destabilizing | 1.57 | Destabilizing | 0.326 | Likely Benign | -5.34 | Deleterious | 0.755 | Possibly Damaging | 0.112 | Benign | 3.37 | Benign | 0.03 | Affected | 0.3899 | 0.0547 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1934T>G | F645C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is inconclusive. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -9.182 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 2.25 | Destabilizing | 0.1 | 2.44 | Destabilizing | 2.35 | Destabilizing | 1.38 | Destabilizing | 0.286 | Likely Benign | -5.41 | Deleterious | 0.967 | Probably Damaging | 0.389 | Benign | 3.35 | Benign | 0.01 | Affected | 0.2421 | 0.1372 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1935T>A | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this view. Overall, the majority of computational evidence points to a pathogenic impact for F645L, 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.159 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1935T>G | F645L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact fall into two groups: benign predictions are made by REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM; pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. No evidence from FoldX‑MD, Rosetta, or premPS is available to alter this conclusion. Overall, the majority of computational evidence points to a pathogenic impact for F645L, and this assessment 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 | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -10.624 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 1.25 | Ambiguous | 1.12 | Ambiguous | 0.99 | Ambiguous | 0.159 | Likely Benign | -4.24 | Deleterious | 0.116 | Benign | 0.008 | Benign | 3.44 | Benign | 0.03 | Affected | 0.2214 | 0.3873 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| 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 | 0.80 | Ambiguous | 0.4 | 1.57 | Ambiguous | 1.19 | Ambiguous | 0.81 | Ambiguous | 0.518 | Likely Pathogenic | -3.75 | Deleterious | 0.994 | Probably Damaging | 0.975 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 3.38 | 31 | 0.2141 | 0.6511 | 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 | 0.92 | Ambiguous | 0.5 | 0.54 | Ambiguous | 0.73 | Ambiguous | 0.84 | Ambiguous | 0.337 | Likely Benign | -2.80 | Deleterious | 0.992 | Probably Damaging | 0.973 | Probably Damaging | 3.24 | Benign | 0.04 | Affected | 0.1049 | 0.6218 | 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 | 1.66 | Ambiguous | 0.7 | 0.39 | Likely Benign | 1.03 | Ambiguous | 0.67 | Ambiguous | 0.443 | Likely Benign | -5.60 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.3195 | 0.5877 | 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 | 2.62 | Destabilizing | 0.7 | 1.63 | Ambiguous | 2.13 | Destabilizing | 0.83 | Ambiguous | 0.510 | Likely Pathogenic | -6.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.2665 | 0.5202 | 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 | 1.72 | Ambiguous | 0.7 | 0.34 | Likely Benign | 1.03 | Ambiguous | 0.37 | Likely Benign | 0.513 | Likely Pathogenic | -6.55 | Deleterious | 0.995 | Probably Damaging | 0.983 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.0618 | 0.6433 | -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 | 1.65 | Ambiguous | 0.7 | 0.80 | Ambiguous | 1.23 | Ambiguous | 0.68 | Ambiguous | 0.171 | Likely Benign | -2.40 | Neutral | 0.986 | Probably Damaging | 0.960 | Probably Damaging | 3.30 | Benign | 0.18 | Tolerated | 0.1657 | 0.4275 | 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 | 1.65 | Ambiguous | 0.7 | 0.80 | Ambiguous | 1.23 | Ambiguous | 0.68 | Ambiguous | 0.171 | Likely Benign | -2.40 | Neutral | 0.986 | Probably Damaging | 0.960 | Probably Damaging | 3.30 | Benign | 0.18 | Tolerated | 0.1657 | 0.4275 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| 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 | 1.73 | Ambiguous | 1.0 | 2.85 | Destabilizing | 2.29 | Destabilizing | 0.98 | Ambiguous | 0.365 | Likely Benign | -1.99 | Neutral | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.01 | Affected | 0.0745 | 0.2033 | 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 | 2.61 | Destabilizing | 0.2 | 3.27 | Destabilizing | 2.94 | Destabilizing | 1.36 | Destabilizing | 0.420 | Likely Benign | -2.98 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.62 | Pathogenic | 0.04 | Affected | 0.1126 | 0.1660 | 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 | 4.92 | Destabilizing | 0.8 | 5.76 | Destabilizing | 5.34 | Destabilizing | 0.91 | Ambiguous | 0.464 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.62 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0566 | 0.1471 | 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 | 4.45 | Destabilizing | 0.3 | 3.47 | Destabilizing | 3.96 | Destabilizing | 2.18 | Destabilizing | 0.758 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.0919 | 0.0488 | -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 | 5.48 | Destabilizing | 0.7 | 10.19 | Destabilizing | 7.84 | Destabilizing | 2.50 | Destabilizing | 0.737 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | 3.37 | 35 | 0.3047 | 0.0625 | -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 | 4.92 | Destabilizing | 0.6 | 5.85 | Destabilizing | 5.39 | Destabilizing | 1.77 | Destabilizing | 0.738 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.1207 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| 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 | -0.33 | Likely Benign | 0.1 | 1.34 | Ambiguous | 0.51 | Ambiguous | 1.01 | Destabilizing | 0.187 | Likely Benign | -1.43 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.24 | Benign | 0.02 | Affected | 3.38 | 25 | 0.0720 | 0.2753 | 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 | 2.34 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.37 | Destabilizing | 0.91 | Ambiguous | 0.121 | Likely Benign | -1.13 | Neutral | 0.976 | Probably Damaging | 0.941 | Probably Damaging | 3.36 | Benign | 0.12 | Tolerated | 0.1272 | 0.2628 | 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 | 2.50 | Destabilizing | 0.1 | 2.06 | Destabilizing | 2.28 | Destabilizing | 1.35 | Destabilizing | 0.575 | Likely Pathogenic | -5.15 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0.1065 | 0.0488 | -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 | 6.30 | Destabilizing | 0.2 | 7.62 | Destabilizing | 6.96 | Destabilizing | 1.28 | Destabilizing | 0.539 | Likely Pathogenic | -5.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.02 | Affected | 0.3426 | 0.1192 | -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 | 1.90 | Ambiguous | 0.5 | 2.62 | Destabilizing | 2.26 | Destabilizing | 1.40 | Destabilizing | 0.554 | Likely Pathogenic | -5.25 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.22 | Benign | 0.01 | Affected | 0.1217 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.886T>A | S296T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S296T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors shows a split: six tools (REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT) and AlphaMissense‑Optimized predict a benign effect, whereas four tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default) predict pathogenicity. ESM1b remains uncertain. High‑accuracy assessments give a more definitive picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the majority of evidence points to a benign 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. | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -7.020 | In-Between | 0.645 | Likely Pathogenic | Likely Benign | 0.09 | Likely Benign | 0.4 | 0.38 | Likely Benign | 0.24 | Likely Benign | 0.19 | Likely Benign | 0.201 | Likely Benign | -2.10 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.13 | Pathogenic | 0.13 | Tolerated | 0.1437 | 0.6340 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.886T>C | S296P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, and SIFT, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. When predictions are grouped by agreement, four tools predict benign and seven predict pathogenic, with premPS remaining uncertain. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Thus, the majority of evidence leans toward pathogenicity, and this conclusion is consistent with the lack of ClinVar annotation and gnomAD absence, which do not contradict the prediction. Overall, 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. | Likely Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -8.302 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.04 | Likely Benign | 0.4 | 0.18 | Likely Benign | 0.11 | Likely Benign | 0.72 | Ambiguous | 0.439 | Likely Benign | -3.74 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.92 | Pathogenic | 0.12 | Tolerated | 0.2273 | 0.6320 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.886T>G | S296A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296A (ClinVar ID 469166.0) is listed as ClinVar status Uncertain and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or neutral. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a benign effect. No evidence from the available tools suggests a deleterious impact. Therefore, the variant is most likely benign, and this conclusion is consistent with its ClinVar status of Uncertain rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | Uncertain | 1 | -6.847 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.3 | -0.26 | Likely Benign | 0.12 | Likely Benign | 0.35 | Likely Benign | 0.209 | Likely Benign | -1.79 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.97 | Pathogenic | 0.65 | Tolerated | 3.40 | 16 | 0.4958 | 0.5522 | 1 | 1 | 2.6 | -16.00 | 182.5 | 26.6 | -0.2 | 0.1 | -0.5 | 0.0 | X | Potentially Pathogenic | The hydroxyl group of the Ser296 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), stably hydrogen bonds with the carboxylate group of Asp330 in a neighboring β strand (res. Ala322-Asp332). The backbone carbonyl group of Ser296 also hydrogen bonds with the guanidinium group of Arg279 in another nearby β strand (res. Arg279-Cys285). In the variant simulations, the methyl group of the Ala296 side chain cannot hydrogen bond with Asp330, causing the carboxylate group positioning to fluctuate more than in the WT simulations.Although the residue swap does not seem to affect the anti-parallel β sheet assembly during the simulations, it is possible that the Ser296-Asp330 hydrogen bond plays a crucial role in maintaining the C2 domain fold. Notably, because Ser296 is located near the membrane interface, the potential effect of the residue swap on the SynGAP-membrane association cannot be addressed by solvent-only simulations. | ||||||||||||||||
| c.887C>A | S296Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and premPS, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic based on predictions, and this assessment 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. | Likely Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -12.148 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.46 | Ambiguous | 0.2 | 0.48 | Likely Benign | 0.97 | Ambiguous | 0.15 | Likely Benign | 0.486 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.05 | Affected | 0.0800 | 0.5610 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.887C>G | S296C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296C 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is 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 benign. No predictions or stability results are missing or inconclusive. 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. | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -7.842 | In-Between | 0.286 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.1 | -0.11 | Likely Benign | 0.18 | Likely Benign | 0.09 | Likely Benign | 0.361 | Likely Benign | -1.46 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.05 | Affected | 0.1052 | 0.6052 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.887C>T | S296F 2D AIThe SynGAP1 missense variant S296F 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 premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive and therefore unavailable as evidence. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -11.721 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.29 | Ambiguous | 1.6 | 0.24 | Likely Benign | 0.77 | Ambiguous | 0.29 | Likely Benign | 0.494 | Likely Benign | -4.34 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.94 | Pathogenic | 0.04 | Affected | 0.0720 | 0.5905 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.739C>A | Q247K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247K (PH domain) is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are REVEL, polyPhen2_HumDiv, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic). High‑accuracy methods all support benignity: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta (combining FoldX‑MD and Rosetta) is benign. Uncertain results from AlphaMissense‑Default and Rosetta are treated as unavailable. Overall, the collective evidence points to a benign impact for Q247K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -10.377 | Likely Pathogenic | 0.502 | Ambiguous | Likely Benign | -0.28 | Likely Benign | 0.1 | 0.74 | Ambiguous | 0.23 | Likely Benign | -0.13 | Likely Benign | 0.529 | Likely Pathogenic | -0.44 | Neutral | 0.787 | Possibly Damaging | 0.351 | Benign | 5.89 | Benign | 0.13 | Tolerated | 0.1366 | 0.2758 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||
| c.739C>G | Q247E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247E 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, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Tools that predict a pathogenic effect are premPS, SIFT, and ESM1b. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign consensus (2 benign vs. 1 pathogenic, with the uncertain result treated as unavailable). High‑accuracy assessments confirm benignity: AlphaMissense‑Optimized is benign, Foldetta (combining FoldX‑MD and Rosetta outputs) is benign, and the SGM Consensus is benign. Overall, the collective evidence indicates that the variant 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. | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -13.564 | Likely Pathogenic | 0.373 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.1 | -0.26 | Likely Benign | 0.08 | Likely Benign | 1.04 | Destabilizing | 0.474 | Likely Benign | -1.46 | Neutral | 0.128 | Benign | 0.039 | Benign | 5.80 | Benign | 0.03 | Affected | 0.1055 | 0.1476 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.740A>C | Q247P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247P 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, while the remaining evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; premPS is uncertain and therefore treated as unavailable. High‑accuracy methods 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. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -14.361 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.43 | Destabilizing | 0.2 | 7.83 | Destabilizing | 5.63 | Destabilizing | 0.81 | Ambiguous | 0.770 | Likely Pathogenic | -3.56 | Deleterious | 0.995 | Probably Damaging | 0.795 | Possibly Damaging | 5.69 | Benign | 0.02 | Affected | 0.1768 | 0.3631 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.740A>G | Q247R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247R 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, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain predictions come from premPS 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 (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, 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 | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -4.022 | Likely Benign | 0.442 | Ambiguous | Likely Benign | -0.38 | Likely Benign | 0.0 | 0.21 | Likely Benign | -0.09 | Likely Benign | -0.91 | Ambiguous | 0.471 | Likely Benign | 1.22 | Neutral | 0.948 | Possibly Damaging | 0.533 | Possibly Damaging | 5.91 | Benign | 1.00 | Tolerated | 0.1196 | 0.1324 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.740A>T | Q247L 2D AIThe SynGAP1 missense variant Q247L 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, 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) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence (seven pathogenic versus three benign predictions) points to a pathogenic impact, and 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. | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -10.554 | Likely Pathogenic | 0.352 | Ambiguous | Likely Benign | -0.86 | Ambiguous | 0.5 | -1.14 | Ambiguous | -1.00 | Ambiguous | 0.38 | Likely Benign | 0.687 | Likely Pathogenic | -3.89 | Deleterious | 0.982 | Probably Damaging | 0.628 | Possibly Damaging | 5.70 | Benign | 0.02 | Affected | 0.0573 | 0.4129 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||
| c.741G>C | Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H 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 SGM‑Consensus, FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Tools that predict a pathogenic outcome are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, 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) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No predictions are missing or inconclusive. 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. | Likely Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -6.239 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.58 | Ambiguous | 0.579 | Likely Pathogenic | -2.10 | Neutral | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.71 | Benign | 0.02 | Affected | 0.0932 | 0.2558 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.741G>T | Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H 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, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Those that predict a pathogenic impact are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default, while premPS is uncertain. 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 benign. No prediction or folding stability result is missing or inconclusive. Based on the overall balance of evidence—seven benign versus five pathogenic predictions, and all high‑accuracy tools indicating benign—the variant is most likely benign. 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 Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -6.239 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.58 | Ambiguous | 0.579 | Likely Pathogenic | -2.10 | Neutral | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.71 | Benign | 0.02 | Affected | 0.0932 | 0.2558 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| 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 | -0.33 | Likely Benign | 0.1 | 0.27 | Likely Benign | -0.03 | Likely Benign | -0.44 | Likely Benign | 0.117 | Likely Benign | -0.06 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.37 | Benign | 0.28 | Tolerated | 0.0625 | 0.3059 | 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 | -1.13 | Ambiguous | 0.1 | 0.54 | Ambiguous | -0.30 | Likely Benign | 0.03 | Likely Benign | 0.180 | Likely Benign | -0.29 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.61 | Benign | 0.90 | Tolerated | 3.37 | 32 | 0.0757 | 0.3477 | 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 | 1.40 | Ambiguous | 0.3 | 0.61 | Ambiguous | 1.01 | Ambiguous | 0.20 | Likely Benign | 0.206 | Likely Benign | -2.62 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.0551 | 0.3055 | -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 | 4.34 | Destabilizing | 0.1 | 3.59 | Destabilizing | 3.97 | Destabilizing | 2.29 | Destabilizing | 0.491 | Likely Benign | -5.33 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.1424 | 0.0541 | -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 | 2.18 | Destabilizing | 0.0 | 2.72 | Destabilizing | 2.45 | Destabilizing | 1.56 | Destabilizing | 0.266 | Likely Benign | -2.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.15 | Tolerated | 0.2456 | 0.2124 | 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 | 3.81 | Destabilizing | 0.1 | 4.62 | Destabilizing | 4.22 | Destabilizing | 2.28 | Destabilizing | 0.499 | Likely Benign | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.1863 | 0.2240 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.910G>A | D304N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant D304N 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, FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to 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 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | Uncertain | 1 | -6.194 | Likely Benign | 0.391 | Ambiguous | Likely Benign | 0.30 | Likely Benign | 0.1 | -0.08 | Likely Benign | 0.11 | Likely Benign | 0.21 | Likely Benign | 0.345 | Likely Benign | -4.18 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.81 | Pathogenic | 0.03 | Affected | 3.38 | 23 | 0.1353 | 0.7205 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||
| c.910G>C | D304H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into three groups: benign predictions come from REVEL, Rosetta, and premPS; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; the remaining tools (FoldX, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy assessments reinforce this pattern: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which is currently absent. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -8.160 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.89 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.53 | Ambiguous | 0.45 | Likely Benign | 0.417 | Likely Benign | -5.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 0.1660 | 0.7498 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.910G>T | D304Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With the majority of evidence pointing toward pathogenicity, the variant is most likely pathogenic; this assessment does not conflict with ClinVar, which contains no entry for D304Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -10.495 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.60 | Ambiguous | 0.2 | 0.14 | Likely Benign | 0.37 | Likely Benign | 0.37 | Likely Benign | 0.468 | Likely Benign | -6.29 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.76 | Pathogenic | 0.00 | Affected | 0.0623 | 0.6566 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.911A>C | D304A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304A variant has no ClinVar entry and is not listed in gnomAD. Prediction tools that classify it as benign include premPS, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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 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 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -6.258 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.77 | Ambiguous | 0.39 | Likely Benign | 0.523 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.80 | Pathogenic | 0.02 | Affected | 0.4457 | 0.6642 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.911A>G | D304G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304G 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, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default, FoldX, Rosetta, and Foldetta are uncertain and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta remaining uncertain. Overall, the majority of tools (five pathogenic vs. four benign) and the SGM Consensus 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. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.713 | Likely Benign | 0.546 | Ambiguous | Likely Benign | 1.02 | Ambiguous | 0.2 | 0.95 | Ambiguous | 0.99 | Ambiguous | 0.47 | Likely Benign | 0.380 | Likely Benign | -5.32 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.02 | Affected | 0.4590 | 0.6451 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.911A>T | D304V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304V 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 Rosetta and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from 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 D304V. This conclusion is not contradicted by ClinVar, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -8.280 | Likely Pathogenic | 0.803 | Likely Pathogenic | Ambiguous | 1.35 | Ambiguous | 0.3 | 0.14 | Likely Benign | 0.75 | Ambiguous | 0.35 | Likely Benign | 0.541 | Likely Pathogenic | -6.22 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0971 | 0.6999 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.912C>A | D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant has no ClinVar entry and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign effect, 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. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.715 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.28 | Likely Benign | 0.48 | Likely Benign | 0.186 | Likely Benign | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.77 | Pathogenic | 0.04 | Affected | 0.1504 | 0.6998 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.912C>G | D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Overall, the balance of evidence favors a benign classification, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.715 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.28 | Likely Benign | 0.48 | Likely Benign | 0.186 | Likely Benign | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.77 | Pathogenic | 0.04 | Affected | 0.1504 | 0.6998 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1378A>C | K460Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K460Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give a pathogenic consensus from the SGM method (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and an uncertain result from AlphaMissense‑Optimized; Foldetta likewise reports no definitive stability change. 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 | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -9.404 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 0.71 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.79 | Ambiguous | 0.86 | Ambiguous | 0.312 | Likely Benign | -3.15 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.14 | Tolerated | 0.4523 | 0.1454 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1378A>G | K460E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K460E 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, a majority of tools predict a pathogenic impact: AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), Rosetta, and premPS all indicate pathogenicity, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No prediction or folding‑stability result is missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K460E, 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 | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -13.304 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.68 | Ambiguous | 0.0 | 2.02 | Destabilizing | 1.85 | Ambiguous | 1.05 | Destabilizing | 0.398 | Likely Benign | -3.40 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.34 | Benign | 0.09 | Tolerated | 0.3966 | 0.1022 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1379A>C | K460T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K460T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s combined FoldX‑MD/Rosetta analysis remains inconclusive. Overall, the majority of evidence points to a pathogenic impact for K460T, 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 | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.187 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 1.23 | Ambiguous | 0.1 | 1.16 | Ambiguous | 1.20 | Ambiguous | 0.77 | Ambiguous | 0.208 | Likely Benign | -5.02 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.35 | Benign | 0.07 | Tolerated | 0.1858 | 0.3848 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1379A>G | K460R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K460R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Taken together, the overwhelming 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 | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -5.349 | Likely Benign | 0.175 | Likely Benign | Likely Benign | -0.41 | Likely Benign | 0.0 | 0.63 | Ambiguous | 0.11 | Likely Benign | 0.55 | Ambiguous | 0.103 | Likely Benign | -1.52 | Neutral | 0.991 | Probably Damaging | 0.962 | Probably Damaging | 3.46 | Benign | 0.63 | Tolerated | 0.5093 | 0.1169 | Weaken | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||
| c.1379A>T | K460M 2D 3DClick to see structure in 3D Viewer AISynGAP1 K460M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: FoldX and AlphaMissense‑Optimized. When high‑accuracy methods are considered separately, AlphaMissense‑Optimized remains inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, 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 | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -10.351 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.0 | 0.18 | Likely Benign | 0.40 | Likely Benign | 0.20 | Likely Benign | 0.252 | Likely Benign | -4.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.29 | Benign | 0.02 | Affected | 0.1148 | 0.4522 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1380G>C | K460N 2D AIThe SynGAP1 missense variant K460N 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, SIFT, and FATHMM, whereas those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic signal: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic; and the protein‑folding stability method Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a benign effect. Overall, the balance of evidence—six pathogenic versus five benign predictions, a pathogenic SGM Consensus, and a pathogenic AlphaMissense‑Optimized—suggests that K460N is most likely pathogenic. This conclusion does not contradict ClinVar status, as the variant is not currently catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.988 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.5 | 0.45 | Likely Benign | 0.35 | Likely Benign | 0.89 | Ambiguous | 0.202 | Likely Benign | -4.13 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.06 | Tolerated | 0.3669 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1380G>T | K460N 2D AIThe SynGAP1 K460N missense variant is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a benign effect. Overall, the majority of evidence—including the high‑accuracy tools—points to a pathogenic impact for K460N. This conclusion is not contradicted by 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 | 0.155435 | Structured | 0.289547 | Uncertain | 0.938 | 0.150 | 0.125 | -11.988 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.5 | 0.45 | Likely Benign | 0.35 | Likely Benign | 0.89 | Ambiguous | 0.202 | Likely Benign | -4.13 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.29 | Benign | 0.06 | Tolerated | 0.3669 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1375G>A | G459S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic impact. 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 | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -10.979 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 2.34 | Destabilizing | 0.1 | 0.77 | Ambiguous | 1.56 | Ambiguous | 0.60 | Ambiguous | 0.414 | Likely Benign | -5.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.09 | Benign | 0.05 | Affected | 0.2340 | 0.5197 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1375G>C | G459R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459R 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 other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score (Likely Pathogenic) all indicate a pathogenic impact. Stability‑based methods (FoldX, Rosetta, premPS) are inconclusive, and Foldetta likewise reports an uncertain effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as Likely Pathogenic, and Foldetta as unavailable. Taken together, the consensus of the majority of tools points to a pathogenic effect for G459R. This prediction 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 | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.958 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.84 | Ambiguous | 0.2 | 0.79 | Ambiguous | 1.32 | Ambiguous | 0.79 | Ambiguous | 0.486 | Likely Benign | -7.41 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.0903 | 0.4248 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1375G>T | G459C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence points to a pathogenic effect for G459C, 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 | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -12.109 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 2.46 | Destabilizing | 0.2 | 1.49 | Ambiguous | 1.98 | Ambiguous | 0.65 | Ambiguous | 0.586 | Likely Pathogenic | -8.46 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.00 | Benign | 0.00 | Affected | 0.0960 | 0.4103 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1376G>A | G459D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G459D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate benign effects include REVEL and FATHMM, while the majority of tools predict pathogenicity: FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta, Foldetta, 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 inconclusive. Overall, the evidence points to a pathogenic effect for G459D, and this conclusion does not conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.258 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.21 | Destabilizing | 0.1 | 0.56 | Ambiguous | 1.39 | Ambiguous | 0.93 | Ambiguous | 0.454 | Likely Benign | -6.18 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.07 | Benign | 0.05 | Affected | 0.1466 | 0.1905 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.1376G>C | G459A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G459A missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled Uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. 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, which integrates FoldX‑MD and Rosetta stability outputs, is Uncertain and therefore not considered evidence. Overall, the majority of reliable tools indicate a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.684 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 2.44 | Destabilizing | 0.1 | 0.90 | Ambiguous | 1.67 | Ambiguous | 0.72 | Ambiguous | 0.469 | Likely Benign | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 0.3529 | 0.5161 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1376G>T | G459V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G459V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms (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 inconclusive and therefore not counted. 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) also predicts pathogenic. Based on the consensus of these predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for G459V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -13.606 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.79 | Destabilizing | 0.1 | 5.01 | Destabilizing | 4.40 | Destabilizing | 0.71 | Ambiguous | 0.605 | Likely Pathogenic | -8.46 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.99 | Benign | 0.00 | Affected | 0.0997 | 0.4240 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| 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 | 0.21 | Likely Benign | 0.0 | -0.07 | Likely Benign | 0.07 | Likely Benign | 0.36 | Likely Benign | 0.021 | Likely Benign | -0.81 | Neutral | 0.300 | Benign | 0.011 | Benign | 4.18 | Benign | 0.14 | Tolerated | 3.38 | 26 | 0.0999 | 0.5574 | 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 | 2.21 | Destabilizing | 0.1 | 6.36 | Destabilizing | 4.29 | Destabilizing | 0.83 | Ambiguous | 0.158 | Likely Benign | -2.46 | Neutral | 0.815 | Possibly Damaging | 0.137 | Benign | 4.09 | Benign | 0.05 | Affected | 0.1624 | 0.4150 | 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 | 0.30 | Likely Benign | 0.0 | 0.62 | Ambiguous | 0.46 | Likely Benign | 0.68 | Ambiguous | 0.012 | Likely Benign | -1.27 | Neutral | 0.042 | Benign | 0.035 | Benign | 4.14 | Benign | 0.15 | Tolerated | 0.2143 | 0.3995 | 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 | 1.60 | Ambiguous | 0.1 | 0.70 | Ambiguous | 1.15 | Ambiguous | 0.92 | Ambiguous | 0.175 | Likely Benign | -3.07 | Deleterious | 0.859 | Possibly Damaging | 0.124 | Benign | 4.10 | Benign | 0.04 | Affected | 0.1490 | 0.1941 | 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 | 1.08 | Ambiguous | 0.1 | 1.78 | Ambiguous | 1.43 | Ambiguous | 0.80 | Ambiguous | 0.034 | Likely Benign | -2.51 | Deleterious | 0.247 | Benign | 0.037 | Benign | 4.12 | Benign | 0.11 | Tolerated | 0.1788 | 0.2719 | 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 | -0.36 | Likely Benign | 0.0 | -0.70 | Ambiguous | -0.53 | Ambiguous | -1.21 | Stabilizing | 0.046 | Likely Benign | 1.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.45 | Benign | 0.97 | Tolerated | 3.38 | 26 | 0.0904 | 0.5292 | 0 | 0 | 2.4 | 28.05 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||
| 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 | 3.38 | Destabilizing | 0.0 | 4.33 | Destabilizing | 3.86 | Destabilizing | 2.47 | Destabilizing | 0.695 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.2124 | 0.0612 | -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 | 2.91 | Destabilizing | 0.1 | 2.88 | Destabilizing | 2.90 | Destabilizing | 1.60 | Destabilizing | 0.646 | Likely Pathogenic | -4.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.64 | Benign | 0.00 | Affected | 3.37 | 35 | 0.2148 | 0.0612 | 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 | 4.98 | Destabilizing | 0.1 | 4.72 | Destabilizing | 4.85 | Destabilizing | 2.49 | Destabilizing | 0.718 | Likely Pathogenic | -9.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 3.37 | 35 | 0.3940 | 0.0612 | -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 | 3.49 | Destabilizing | 0.1 | 4.86 | Destabilizing | 4.18 | Destabilizing | 2.33 | Destabilizing | 0.559 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.61 | Benign | 0.00 | Affected | 0.4056 | 0.1945 | -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 | 3.41 | Destabilizing | 0.5 | 4.37 | Destabilizing | 3.89 | Destabilizing | 2.32 | Destabilizing | 0.578 | Likely Pathogenic | -8.95 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.3203 | 0.1814 | 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 | 0.40 | Likely Benign | 0.0 | 0.76 | Ambiguous | 0.58 | Ambiguous | 0.69 | Ambiguous | 0.434 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.93 | Benign | 0.07 | Tolerated | 0.2409 | 0.2598 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.1381G>A | A461T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A461T 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, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta is also inconclusive. Overall, the balance of evidence favors a benign 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. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.885 | Likely Pathogenic | 0.323 | Likely Benign | Likely Benign | 1.21 | Ambiguous | 0.2 | 0.51 | Ambiguous | 0.86 | Ambiguous | 0.65 | Ambiguous | 0.214 | Likely Benign | -3.27 | Deleterious | 0.508 | Possibly Damaging | 0.042 | Benign | 3.40 | Benign | 0.13 | Tolerated | 0.1083 | 0.5930 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.1381G>C | A461P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -13.869 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | -0.35 | Likely Benign | 0.1 | 5.09 | Destabilizing | 2.37 | Destabilizing | 0.84 | Ambiguous | 0.451 | Likely Benign | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.32 | Benign | 0.03 | Affected | 0.1748 | 0.3949 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1381G>T | A461S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 (HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv), SIFT, and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are not considered evidence for either side. 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 also unavailable. Overall, the balance of evidence leans toward a benign 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. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -10.663 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.87 | Ambiguous | 0.0 | 1.18 | Ambiguous | 1.03 | Ambiguous | 0.63 | Ambiguous | 0.236 | Likely Benign | -2.74 | Deleterious | 0.600 | Possibly Damaging | 0.289 | Benign | 3.36 | Benign | 0.02 | Affected | 0.2401 | 0.4551 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1382C>A | A461D 2D AIThe SynGAP1 missense variant A461D 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. The majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that A461D 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 | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -14.918 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.89 | Ambiguous | 1.1 | 2.18 | Destabilizing | 1.54 | Ambiguous | 1.09 | Destabilizing | 0.477 | Likely Benign | -5.47 | Deleterious | 0.997 | Probably Damaging | 0.792 | Possibly Damaging | 3.32 | Benign | 0.01 | Affected | 0.1533 | 0.2016 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1382C>G | A461G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461G has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into three groups: benign predictions come from REVEL, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; the remaining tools (FoldX, premPS, AlphaMissense‑Default, Foldetta) 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 pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, with no ClinVar record 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 | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -11.360 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 1.46 | Ambiguous | 0.1 | 2.06 | Destabilizing | 1.76 | Ambiguous | 0.83 | Ambiguous | 0.276 | Likely Benign | -3.79 | Deleterious | 0.991 | Probably Damaging | 0.628 | Possibly Damaging | 3.32 | Benign | 0.00 | Affected | 0.1988 | 0.3317 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.1382C>T | A461V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A461V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and ESM1b. 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. Because the majority of standard predictors (nine benign vs. three pathogenic) favor a benign outcome, 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. | GAP | 0.179055 | Structured | 0.292531 | Uncertain | 0.936 | 0.151 | 0.125 | -9.968 | Likely Pathogenic | 0.436 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.3 | 0.34 | Likely Benign | 0.13 | Likely Benign | 0.02 | Likely Benign | 0.141 | Likely Benign | -3.05 | Deleterious | 0.983 | Probably Damaging | 0.273 | Benign | 3.43 | Benign | 0.66 | Tolerated | 0.0819 | 0.5078 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| 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 | 3.06 | Destabilizing | 0.2 | 2.40 | Destabilizing | 2.73 | Destabilizing | 0.63 | Ambiguous | 0.558 | Likely Pathogenic | -3.95 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.1187 | 0.5050 | 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 | 5.42 | Destabilizing | 0.0 | 8.74 | Destabilizing | 7.08 | Destabilizing | 1.16 | Destabilizing | 0.650 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 0.1758 | 0.3626 | 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 | 1.18 | Ambiguous | 0.1 | 1.97 | Ambiguous | 1.58 | Ambiguous | 0.55 | Ambiguous | 0.310 | Likely Benign | -2.96 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.27 | Benign | 0.06 | Tolerated | 0.2420 | 0.3471 | 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 | 8.13 | Destabilizing | 0.2 | 4.35 | Destabilizing | 6.24 | Destabilizing | 1.40 | Destabilizing | 0.662 | Likely Pathogenic | -5.93 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.00 | Affected | 0.1541 | 0.1741 | 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 | 1.76 | Ambiguous | 0.0 | 2.45 | Destabilizing | 2.11 | Destabilizing | 1.00 | Destabilizing | 0.378 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.15 | Benign | 0.06 | Tolerated | 0.2135 | 0.2936 | 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 | 3.31 | Destabilizing | 0.2 | 1.80 | Ambiguous | 2.56 | Destabilizing | 0.66 | Ambiguous | 0.487 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.26 | Benign | 0.02 | Affected | 0.0950 | 0.4955 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.772C>A | R258S 2D AIThe SynGAP1 missense variant R258S is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, 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 outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for R258S, and this conclusion is consistent with the absence of ClinVar annotation or gnomAD frequency data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.295083 | Structured | 0.293667 | Uncertain | 0.894 | 0.260 | 0.250 | -14.336 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.11 | Destabilizing | 0.8 | 1.29 | Ambiguous | 1.70 | Ambiguous | 1.14 | Destabilizing | 0.796 | Likely Pathogenic | -4.92 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.89 | Benign | 0.01 | Affected | 0.3057 | 0.3881 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.772C>G | R258G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R258G is not reported in ClinVar and is absent from gnomAD. 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, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as pathogenic; premPS remains uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction is missing or inconclusive. Consequently, 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 | C2 | 0.295083 | Structured | 0.293667 | Uncertain | 0.894 | 0.260 | 0.250 | -14.239 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 2.42 | Destabilizing | 0.5 | 2.33 | Destabilizing | 2.38 | Destabilizing | 0.94 | Ambiguous | 0.788 | Likely Pathogenic | -5.83 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.78 | Benign | 0.04 | Affected | 0.3166 | 0.3447 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.772C>T | R258C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R258C missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437677‑C‑T). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. 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 | 0.295083 | Structured | 0.293667 | Uncertain | 0.894 | 0.260 | 0.250 | Uncertain | 1 | 6-33437677-C-T | 1 | 6.20e-7 | -10.285 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 1.17 | Ambiguous | 0.4 | 1.76 | Ambiguous | 1.47 | Ambiguous | 0.87 | Ambiguous | 0.771 | Likely Pathogenic | -6.79 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 5.77 | Benign | 0.00 | Affected | 3.39 | 15 | 0.3307 | 0.3411 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| c.773G>A | R258H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R258H is listed as Benign in ClinVar (ID 949697.0) and is present in gnomAD (6‑33437678‑G‑A). Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain calls come from FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. The high‑accuracy consensus (SGM) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized remains benign, while Foldetta is inconclusive. Overall, the majority of evidence points to a pathogenic impact, which contradicts the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.295083 | Structured | 0.293667 | Uncertain | 0.894 | 0.260 | 0.250 | Benign/Likely benign | 3 | 6-33437678-G-A | 10 | 6.20e-6 | -10.533 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 1.60 | Ambiguous | 0.6 | 1.00 | Ambiguous | 1.30 | Ambiguous | 1.47 | Destabilizing | 0.830 | Likely Pathogenic | -4.06 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 5.77 | Benign | 0.01 | Affected | 3.39 | 15 | 0.2925 | 0.1980 | 2 | 0 | 1.3 | -19.05 | 212.5 | 81.8 | 0.1 | 0.0 | -0.5 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg258, located at the end of an α-β loop connecting the PH domain to the C2 domain (res. Lys251-Arg258), forms hydrogen bonds with the carboxamide groups of Asn727 and Asn729 side chains, as well as with the backbone carbonyl groups of Ala724, Leu725, and Asn727 in the WT simulations. Although the imidazole group of His258 can act as a hydrogen bond donor/acceptor, the swapped residue is unable to maintain an equally well-coordinated hydrogen bond network for linking the C2 and GAP domains in the variant simulations. | ||||||||||||||
| c.773G>C | R258P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R258P is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FATHMM predicts a benign outcome. Predictions of uncertain status come from FoldX, Rosetta, and Foldetta. High‑accuracy tools reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains inconclusive. Overall, the preponderance of evidence supports a pathogenic classification for R258P, 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. | Likely Pathogenic | C2 | 0.295083 | Structured | 0.293667 | Uncertain | 0.894 | 0.260 | 0.250 | -14.293 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.26 | Ambiguous | 0.4 | 0.92 | Ambiguous | 1.09 | Ambiguous | 1.00 | Destabilizing | 0.924 | Likely Pathogenic | -5.83 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 0.2148 | 0.4557 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.773G>T | R258L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R258L is not reported in ClinVar and is present in gnomAD (ID 6‑33437678‑G‑T). Prediction tools that agree on a benign effect include FoldX, Rosetta, FATHMM, and the combined Foldetta stability method. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools give inconclusive results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic 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. | Likely Pathogenic | C2 | 0.295083 | Structured | 0.293667 | Uncertain | 0.894 | 0.260 | 0.250 | 6-33437678-G-T | 1 | 6.20e-7 | -13.302 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 0.14 | Likely Benign | 0.2 | 0.10 | Likely Benign | 0.12 | Likely Benign | 0.52 | Ambiguous | 0.908 | Likely Pathogenic | -5.90 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.84 | Benign | 0.01 | Affected | 3.39 | 15 | 0.1606 | 0.4602 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||
| 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 | 3.05 | Destabilizing | 0.2 | 5.36 | Destabilizing | 4.21 | Destabilizing | 0.78 | Ambiguous | 0.557 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.06 | Tolerated | 0.2098 | 0.5395 | 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 | 0.36 | Likely Benign | 0.0 | 0.31 | Likely Benign | 0.34 | Likely Benign | 0.56 | Ambiguous | 0.358 | Likely Benign | -4.27 | Deleterious | 0.995 | Probably Damaging | 0.960 | Probably Damaging | 3.40 | Benign | 0.15 | Tolerated | 0.4137 | 0.4257 | 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 | 0.44 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.40 | Likely Benign | 0.55 | Ambiguous | 0.260 | Likely Benign | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.48 | Benign | 0.13 | Tolerated | 0.3525 | 0.4349 | 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 | -0.59 | Ambiguous | 0.1 | -0.26 | Likely Benign | -0.43 | Likely Benign | 0.80 | Ambiguous | 0.373 | Likely Benign | -5.23 | Deleterious | 0.999 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.14 | Tolerated | 0.1153 | 0.3326 | 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 | -0.81 | Ambiguous | 0.1 | -0.11 | Likely Benign | -0.46 | Likely Benign | 0.61 | Ambiguous | 0.390 | Likely Benign | -5.26 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.52 | Benign | 0.20 | Tolerated | 0.1016 | 0.3013 | -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 | -0.40 | Likely Benign | 0.1 | 0.29 | Likely Benign | -0.06 | Likely Benign | 0.50 | Likely Benign | 0.337 | Likely Benign | -4.76 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.09 | Tolerated | 0.0724 | 0.6128 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.2074C>A | L692M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692M 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. Tools that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 (2 vs 2) and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Thus, the overall evidence slightly favors pathogenicity, with a majority of standard tools predicting a deleterious impact. 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 change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -9.659 | Likely Pathogenic | 0.746 | Likely Pathogenic | Likely Benign | 0.49 | Likely Benign | 0.0 | 1.81 | Ambiguous | 1.15 | Ambiguous | 1.01 | Destabilizing | 0.302 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.0754 | 0.2585 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2074C>G | L692V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692V 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. All other evaluated tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized indicates benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for 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 | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -11.441 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 3.29 | Destabilizing | 0.1 | 2.91 | Destabilizing | 3.10 | Destabilizing | 1.57 | Destabilizing | 0.286 | Likely Benign | -2.99 | Deleterious | 0.978 | Probably Damaging | 0.606 | Possibly Damaging | 3.12 | Benign | 0.01 | Affected | 0.1395 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.2075T>A | L692Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692Q is listed in ClinVar as Pathogenic (ClinVar ID 2714634.0) 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 and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; 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, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, 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 | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | Pathogenic | 1 | -13.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.24 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.26 | Destabilizing | 2.76 | Destabilizing | 0.596 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | 0.1079 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.2075T>C | L692P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692P is listed in ClinVar with an “Uncertain” status (ClinVar ID 847082.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools (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 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 outputs, also predicts pathogenic. Based on the overwhelming consensus 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 | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | Uncertain | 1 | -16.447 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 9.19 | Destabilizing | 0.1 | 13.20 | Destabilizing | 11.20 | Destabilizing | 1.69 | Destabilizing | 0.668 | Likely Pathogenic | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | 0.3642 | 0.1025 | -3 | -3 | -5.4 | -16.04 | 186.2 | 62.8 | -0.2 | 0.1 | -0.7 | 0.3 | X | Potentially Pathogenic | The isobutyl side chain of Leu692, located in the middle of an α-helix (res. Leu685-Gln702), engages in hydrophobic packing with nearby residues (e.g., Leu441, Leu431, Leu696) in the inter-helix space. Prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Glu688 in the same manner as Leu692 in the WT. Consequently, the residue swap with proline disrupts the continuity of the secondary structure element in the variant simulations. Additionally, the side chain of Pro692 is not as optimal as Leu692 for hydrophobic packing in the inter-helix space. | ||||||||||||||||
| c.2075T>G | L692R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692R 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 | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -16.656 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.34 | Destabilizing | 0.0 | 5.51 | Destabilizing | 4.93 | Destabilizing | 1.96 | Destabilizing | 0.611 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.07 | Benign | 0.00 | Affected | 0.1204 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.883A>C | T295P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX and AlphaMissense‑Optimized, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. High‑accuracy assessments further show that AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as likely pathogenic, and Foldetta reports an uncertain stability change. With the majority of evidence pointing to deleterious effects, the variant is most likely pathogenic, 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 | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -9.941 | Likely Pathogenic | 0.688 | Likely Pathogenic | Likely Benign | 0.26 | Likely Benign | 0.2 | 3.30 | Destabilizing | 1.78 | Ambiguous | 0.60 | Ambiguous | 0.531 | Likely Pathogenic | -4.65 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2442 | 0.5327 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.883A>G | T295A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign (REVEL, FoldX, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). Four tools are uncertain (Rosetta, Foldetta, premPS, 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 inconclusive. Overall, the majority of conventional predictors lean toward a benign effect, whereas the SGM Consensus indicates a pathogenic signal. Thus, the variant is most likely benign based on the bulk of 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. | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -7.276 | In-Between | 0.336 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | 1.17 | Ambiguous | 0.70 | Ambiguous | 0.56 | Ambiguous | 0.340 | Likely Benign | -3.51 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.96 | Pathogenic | 0.11 | Tolerated | 0.4623 | 0.4190 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||
| c.883A>T | T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant 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 | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -4.904 | Likely Benign | 0.335 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.2 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.54 | Ambiguous | 0.218 | Likely Benign | -2.16 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.14 | Tolerated | 0.3910 | 0.4473 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.884C>A | T295N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295N 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 include REVEL, FoldX, ESM1b, and Foldetta, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. 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, seven tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -6.588 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.24 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.45 | Likely Benign | 0.89 | Ambiguous | 0.438 | Likely Benign | -3.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.03 | Affected | 0.1522 | 0.4457 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.884C>G | T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant 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 | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -4.904 | Likely Benign | 0.335 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.2 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.54 | Ambiguous | 0.196 | Likely Benign | -2.16 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.14 | Tolerated | 0.3910 | 0.4473 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.884C>T | T295I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T295I is reported in gnomAD (ID 6‑33437789‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two consensus groups: benign predictions come from FoldX and Foldetta, while pathogenic predictions are supported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by AlphaMissense‑Optimized, Rosetta, and premPS and are treated as inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect, with only a minority of tools indicating benign or uncertain outcomes. 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 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | 6-33437789-C-T | 4 | 2.48e-6 | -9.330 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.21 | Likely Benign | 0.2 | 0.55 | Ambiguous | 0.38 | Likely Benign | 0.58 | Ambiguous | 0.607 | Likely Pathogenic | -4.87 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.04 | Affected | 3.38 | 23 | 0.1025 | 0.5599 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| c.796C>A | L266M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266M 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, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of tools (six benign vs. four pathogenic, with two uncertain) lean toward a benign classification, and this conclusion is not contradicted by ClinVar status. Thus, the variant is most likely benign based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -9.740 | Likely Pathogenic | 0.362 | Ambiguous | Likely Benign | 0.07 | Likely Benign | 0.1 | -0.47 | Likely Benign | -0.20 | Likely Benign | 0.95 | Ambiguous | 0.288 | Likely Benign | -1.66 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.55 | Pathogenic | 0.07 | Tolerated | 0.0581 | 0.2853 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.796C>G | L266V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L266V 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are therefore considered unavailable. 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) and Foldetta is also inconclusive. Consequently, the variant is most likely benign based on the current predictions, and this assessment does not contradict ClinVar, which has no reported status for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -8.586 | Likely Pathogenic | 0.153 | Likely Benign | Likely Benign | 1.71 | Ambiguous | 0.1 | 0.97 | Ambiguous | 1.34 | Ambiguous | 1.32 | Destabilizing | 0.193 | Likely Benign | -2.20 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.37 | Pathogenic | 0.11 | Tolerated | 0.1152 | 0.2456 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.797T>A | L266Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L266Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect: none. Tools that agree on a pathogenic effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The only tool with an uncertain outcome is Rosetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on the overwhelming agreement among these 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 | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -16.672 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.92 | Destabilizing | 0.1 | 1.49 | Ambiguous | 2.21 | Destabilizing | 2.21 | Destabilizing | 0.563 | Likely Pathogenic | -5.25 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0815 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.797T>C | L266P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266P 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 corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No conflicting benign evidence is present. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -15.752 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.08 | Destabilizing | 0.1 | 4.02 | Destabilizing | 5.55 | Destabilizing | 2.31 | Destabilizing | 0.654 | Likely Pathogenic | -6.06 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.3158 | 0.1021 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.797T>G | L266R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266R 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 in the dataset predicts a benign effect, so the benign‑prediction group is empty. 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) predicts pathogenic. Based on the collective evidence, 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 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -17.131 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.2 | 2.76 | Destabilizing | 3.37 | Destabilizing | 2.04 | Destabilizing | 0.574 | Likely Pathogenic | -5.32 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.1059 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| 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 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.468 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 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 | 0.86 | Ambiguous | 0.0 | 0.87 | Ambiguous | 0.87 | Ambiguous | 0.65 | Ambiguous | 0.382 | Likely Benign | -3.82 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.35 | Benign | 0.13 | Tolerated | 0.2735 | 0.4074 | 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 | -0.12 | Likely Benign | 0.0 | -0.79 | Ambiguous | -0.46 | Likely Benign | 0.56 | Ambiguous | 0.497 | Likely Benign | -4.81 | Deleterious | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.0865 | 0.6284 | 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 | 0.19 | Likely Benign | 0.0 | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.67 | Ambiguous | 0.241 | Likely Benign | -2.76 | Deleterious | 0.940 | Possibly Damaging | 0.843 | Possibly Damaging | 3.28 | Benign | 0.06 | Tolerated | 0.1015 | 0.4980 | 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 | 0.82 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.13 | Likely Benign | 0.38 | Likely Benign | 0.273 | Likely Benign | -2.83 | Deleterious | 0.866 | Possibly Damaging | 0.780 | Possibly Damaging | 3.34 | Benign | 0.09 | Tolerated | 0.1154 | 0.6487 | 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 | -0.26 | Likely Benign | 0.3 | -0.96 | Ambiguous | -0.61 | Ambiguous | 0.65 | Ambiguous | 0.557 | Likely Pathogenic | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.34 | Benign | 0.02 | Affected | 0.0779 | 0.6095 | -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 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.343 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 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 | -1.04 | Ambiguous | 0.0 | -0.06 | Likely Benign | -0.55 | Ambiguous | 0.74 | Ambiguous | 0.343 | Likely Benign | -4.47 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.30 | Benign | 0.05 | Affected | 0.0781 | 0.3426 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1384A>C | K462Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K462Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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) as benign. Overall, the majority of tools and the protein‑stability analysis favor a benign effect, while the consensus pathogenic score introduces uncertainty. Thus, the variant is most likely benign; this assessment does not contradict ClinVar status, which has no entry for K462Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -12.144 | Likely Pathogenic | 0.809 | Likely Pathogenic | Ambiguous | 0.12 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.23 | Likely Benign | 0.48 | Likely Benign | 0.384 | Likely Benign | -3.85 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.40 | Benign | 0.15 | Tolerated | 0.4639 | 0.1286 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1384A>G | K462E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K462E 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, 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. Rosetta and Foldetta are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta is uncertain. Overall, the majority of predictions (7 pathogenic vs. 5 benign) and the high‑accuracy tools support a pathogenic classification. Thus, 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 | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -14.696 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.0 | 1.56 | Ambiguous | 0.95 | Ambiguous | 0.33 | Likely Benign | 0.433 | Likely Benign | -3.88 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.49 | Benign | 0.15 | Tolerated | 0.4145 | 0.1022 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1385A>C | K462T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K462T 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, premPS, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points toward 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 | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -11.586 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.0 | 1.08 | Ambiguous | 0.82 | Ambiguous | 0.30 | Likely Benign | 0.414 | Likely Benign | -5.82 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.47 | Benign | 0.08 | Tolerated | 0.2095 | 0.3257 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1385A>G | K462R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K462R is catalogued in gnomAD (ID 6‑33438290‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Three tools (Rosetta, Foldetta, premPS) yield 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) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is uncertain, so neither provides decisive evidence. Overall, the majority of reliable predictors lean toward a benign effect. This consensus does not contradict ClinVar status, which is currently absent. Thus, based on available predictions, K462R is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | 6-33438290-A-G | 1 | 6.20e-7 | -9.980 | Likely Pathogenic | 0.184 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.1 | 0.90 | Ambiguous | 0.52 | Ambiguous | 0.84 | Ambiguous | 0.246 | Likely Benign | -2.75 | Deleterious | 0.983 | Probably Damaging | 0.962 | Probably Damaging | 3.43 | Benign | 0.09 | Tolerated | 3.37 | 34 | 0.4995 | 0.1201 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||
| c.1385A>T | K462M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K462M missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, FATHMM, premPS, and the protein‑folding stability method Foldetta; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Rosetta’s output is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also pathogenic, while Foldetta indicates a benign effect on protein stability. No evidence from ClinVar contradicts these findings. Overall, the majority of predictive tools and the consensus score support a pathogenic classification, suggesting that K462M is most likely pathogenic rather than benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -12.837 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | -0.23 | Likely Benign | 0.1 | 0.86 | Ambiguous | 0.32 | Likely Benign | 0.17 | Likely Benign | 0.475 | Likely Benign | -5.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.1282 | 0.3932 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1386G>C | K462N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K462N 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 PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, and the SGM Consensus also indicates Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result, providing no definitive evidence. Overall, the majority of high‑confidence predictors lean toward pathogenicity, contradicting the absence of a ClinVar classification. 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. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | -12.823 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.1 | 1.67 | Ambiguous | 1.18 | Ambiguous | 0.90 | Ambiguous | 0.304 | Likely Benign | -4.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 3.37 | 34 | 0.3967 | 0.1242 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||
| c.1386G>T | K462N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K462N is reported in gnomAD (ID 6‑33438291‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K462N. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.297737 | Uncertain | 0.921 | 0.159 | 0.125 | 6-33438291-G-T | 1 | 6.20e-7 | -12.823 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.1 | 1.67 | Ambiguous | 1.18 | Ambiguous | 0.90 | Ambiguous | 0.303 | Likely Benign | -4.83 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.42 | Benign | 0.07 | Tolerated | 3.37 | 34 | 0.3967 | 0.1242 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||
| c.799T>A | W267R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267R has no ClinVar entry and is not reported in gnomAD. Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic or likely pathogenic scores. Tools that are inconclusive (FoldX and premPS) are noted as uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No benign predictions are present. Consequently, 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 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -13.868 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.1 | 2.47 | Destabilizing | 2.21 | Destabilizing | 0.51 | Ambiguous | 0.672 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.00 | Pathogenic | 0.01 | Affected | 0.3763 | 0.0571 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||
| c.799T>C | W267R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267R is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tools predict a benign outcome. Uncertain predictions are provided by FoldX and premPS. High‑accuracy methods give the following 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 collective 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 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -13.868 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.94 | Ambiguous | 0.1 | 2.47 | Destabilizing | 2.21 | Destabilizing | 0.51 | Ambiguous | 0.672 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.00 | Pathogenic | 0.01 | Affected | 0.3763 | 0.0571 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||
| c.799T>G | W267G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods corroborate this: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, 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 | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -15.020 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.40 | Destabilizing | 0.2 | 3.99 | Destabilizing | 4.20 | Destabilizing | 1.20 | Destabilizing | 0.678 | Likely Pathogenic | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.96 | Pathogenic | 0.03 | Affected | 0.4049 | 0.1481 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.800G>C | W267S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267S is not listed in ClinVar and has no allele in gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all report pathogenicity; premPS is uncertain. 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) is pathogenic. 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 | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -12.833 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.3 | 3.20 | Destabilizing | 3.31 | Destabilizing | 0.87 | Ambiguous | 0.593 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.03 | Pathogenic | 0.09 | Tolerated | 0.3809 | 0.1415 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||
| c.800G>T | W267L 2D AIThe SynGAP1 missense variant W267L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign effect. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. High‑accuracy assessments further support a damaging effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” while Foldetta’s stability prediction is uncertain. Overall, the evidence strongly indicates that W267L is most likely pathogenic, and this conclusion 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 | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -13.670 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.19 | Ambiguous | 0.7 | 1.31 | Ambiguous | 1.25 | Ambiguous | 0.75 | Ambiguous | 0.628 | Likely Pathogenic | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.93 | Pathogenic | 0.01 | Affected | 0.2122 | 0.2843 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||
| c.801G>C | W267C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it 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: 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 pathogenic. Thus, the variant is most likely pathogenic based on the consensus of all predictions, 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 | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -12.351 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.2 | 2.20 | Destabilizing | 2.51 | Destabilizing | 1.00 | Destabilizing | 0.705 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.01 | Affected | 0.3573 | 0.1700 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.801G>T | W267C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267C is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it 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: 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 pathogenic. Thus, the variant is most likely pathogenic based on the consensus of all predictions, 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 | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -12.351 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.2 | 2.20 | Destabilizing | 2.51 | Destabilizing | 1.00 | Destabilizing | 0.705 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.01 | Affected | 0.3573 | 0.1700 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.913A>C | T305P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305P 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM; premPS is uncertain. 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‑vs‑2 split. Overall, the majority of tools (7 pathogenic vs. 5 benign) lean toward a pathogenic impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -5.203 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 3.64 | Destabilizing | 1.1 | 6.02 | Destabilizing | 4.83 | Destabilizing | 0.71 | Ambiguous | 0.293 | Likely Benign | -2.83 | Deleterious | 0.997 | Probably Damaging | 0.929 | Probably Damaging | 1.72 | Pathogenic | 0.06 | Tolerated | 0.2206 | 0.5333 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| c.913A>G | T305A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305A variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437818‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. 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 majority of evidence points to a benign impact, 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 | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | Conflicting | 2 | 6-33437818-A-G | 13 | 8.05e-6 | -4.307 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 1.30 | Ambiguous | 0.6 | 1.55 | Ambiguous | 1.43 | Ambiguous | 0.77 | Ambiguous | 0.144 | Likely Benign | -2.10 | Neutral | 0.939 | Possibly Damaging | 0.645 | Possibly Damaging | 1.76 | Pathogenic | 0.12 | Tolerated | 3.40 | 20 | 0.4277 | 0.4403 | 1 | 0 | 2.5 | -30.03 | 177.9 | 43.5 | -0.2 | 0.1 | 0.4 | 0.0 | Uncertain | The hydroxyl group of Thr305, located at the beginning of an anti-parallel β strand (res. Thr305-Asn315), hydrogen bonds with the carboxylate groups of Glu270 and Asp304 in the anti-parallel β strand and the adjacent β hairpin loop, respectively. In the variant simulations, the methyl group of the Ala305 side chain cannot hydrogen bond with either of the acidic residues, which could weaken the integrity of the tertiary structure and the β hairpin loop. Indeed, the guanidinium group of Arg299 does not acquire its central hairpin loop position due to the residue swap.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | ||||||||||||||
| c.913A>T | T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. 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 calculations, yields an uncertain result. Overall, the majority of evidence points to 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 | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -2.899 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.4 | 1.21 | Ambiguous | 0.83 | Ambiguous | 0.55 | Ambiguous | 0.135 | Likely Benign | -0.60 | Neutral | 0.760 | Possibly Damaging | 0.484 | Possibly Damaging | 1.86 | Pathogenic | 0.54 | Tolerated | 0.3579 | 0.4496 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.914C>A | T305N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T305N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign, and the SGM‑Consensus score is “Likely Benign.” Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, and the combined Foldetta) return 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, and PROVEAN) is also benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact for T305N, 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 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -3.261 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 1.18 | Ambiguous | 0.2 | 1.65 | Ambiguous | 1.42 | Ambiguous | 0.09 | Likely Benign | 0.098 | Likely Benign | 0.71 | Neutral | 0.046 | Benign | 0.040 | Benign | 2.34 | Pathogenic | 0.67 | Tolerated | 0.1327 | 0.4352 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.914C>G | T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. 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 calculations, yields an uncertain result. Overall, the majority of evidence points to 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 | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -2.899 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.4 | 1.21 | Ambiguous | 0.83 | Ambiguous | 0.55 | Ambiguous | 0.104 | Likely Benign | -0.60 | Neutral | 0.760 | Possibly Damaging | 0.484 | Possibly Damaging | 1.86 | Pathogenic | 0.54 | Tolerated | 0.3579 | 0.4496 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.914C>T | T305I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437819‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the balance of evidence from high‑confidence predictors leans toward a benign impact, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | Uncertain | 1 | 6-33437819-C-T | 1 | 6.20e-7 | -5.222 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.58 | Ambiguous | 0.48 | Likely Benign | 0.25 | Likely Benign | 0.224 | Likely Benign | -2.90 | Deleterious | 0.997 | Probably Damaging | 0.929 | Probably Damaging | 1.70 | Pathogenic | 0.04 | Affected | 3.40 | 20 | 0.0939 | 0.5693 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||
| 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 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.145 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 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 | 0.47 | Likely Benign | 0.0 | 0.55 | Ambiguous | 0.51 | Ambiguous | 0.85 | Ambiguous | 0.116 | Likely Benign | -2.32 | Neutral | 0.948 | Possibly Damaging | 0.124 | Benign | 3.35 | Benign | 0.13 | Tolerated | 3.37 | 32 | 0.2600 | 0.3718 | 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 | 0.48 | Likely Benign | 0.0 | -0.31 | Likely Benign | 0.09 | Likely Benign | -0.57 | Ambiguous | 0.067 | Likely Benign | 0.48 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.32 | Benign | 0.21 | Tolerated | 0.0864 | 0.5012 | 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 | 0.38 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.18 | Likely Benign | 0.81 | Ambiguous | 0.070 | Likely Benign | -2.31 | Neutral | 0.372 | Benign | 0.026 | Benign | 3.37 | Benign | 0.18 | Tolerated | 3.37 | 32 | 0.1085 | 0.3767 | 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 | 0.36 | Likely Benign | 0.1 | -0.46 | Likely Benign | -0.05 | Likely Benign | -0.15 | Likely Benign | 0.039 | Likely Benign | -1.48 | Neutral | 0.038 | Benign | 0.008 | Benign | 3.42 | Benign | 0.33 | Tolerated | 0.1219 | 0.5077 | 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 | 0.04 | Likely Benign | 0.1 | -1.39 | Ambiguous | -0.68 | Ambiguous | 0.13 | Likely Benign | 0.105 | Likely Benign | -3.23 | Deleterious | 0.559 | Possibly Damaging | 0.044 | Benign | 3.40 | Benign | 0.14 | Tolerated | 0.0756 | 0.5006 | -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 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.168 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 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 | -0.69 | Ambiguous | 0.2 | -1.33 | Ambiguous | -1.01 | Ambiguous | 0.50 | Likely Benign | 0.167 | Likely Benign | -3.36 | Deleterious | 0.950 | Possibly Damaging | 0.214 | Benign | 3.40 | Benign | 0.18 | Tolerated | 0.0762 | 0.3250 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.736C>A | L246M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include PROVEAN and FATHMM, while a majority (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are uncertain. High‑accuracy methods are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Thus no high‑accuracy tool provides a definitive verdict. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any ClinVar status because no ClinVar record exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -11.386 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.65 | Ambiguous | 0.2 | 0.76 | Ambiguous | 0.71 | Ambiguous | 0.87 | Ambiguous | 0.661 | Likely Pathogenic | -1.79 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.72 | Benign | 0.01 | Affected | 0.0710 | 0.3511 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.736C>G | L246V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L246V is reported in gnomAD (variant ID 6‑33435587‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Only FATHMM predicts a benign outcome. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. The overwhelming majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | 6-33435587-C-G | 1 | 6.20e-7 | -12.092 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 2.09 | Destabilizing | 0.1 | 1.52 | Ambiguous | 1.81 | Ambiguous | 1.13 | Destabilizing | 0.736 | Likely Pathogenic | -2.60 | Deleterious | 0.930 | Possibly Damaging | 0.504 | Possibly Damaging | 4.71 | Benign | 0.01 | Affected | 3.41 | 14 | 0.1434 | 0.3607 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.737T>A | L246Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to 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 impact; Rosetta is uncertain and is not grouped. 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 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 | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -15.420 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.3 | 1.79 | Ambiguous | 2.31 | Destabilizing | 1.69 | Destabilizing | 0.921 | Likely Pathogenic | -5.43 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.1092 | 0.0758 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.737T>C | L246P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from FATHMM, while 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 effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates 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 consensus of these 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. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -16.581 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.42 | Destabilizing | 0.3 | 8.72 | Destabilizing | 7.57 | Destabilizing | 1.79 | Destabilizing | 0.944 | Likely Pathogenic | -6.30 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.3731 | 0.1582 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.737T>G | L246R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246R missense variant 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 tools—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 reports 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. No prediction or folding stability 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 status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -13.849 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.94 | Destabilizing | 0.8 | 2.77 | Destabilizing | 3.36 | Destabilizing | 1.72 | Destabilizing | 0.925 | Likely Pathogenic | -5.43 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.1266 | 0.0600 | -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 | 0.21 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.22 | Likely Benign | 0.78 | Ambiguous | 0.391 | Likely Benign | -3.75 | Deleterious | 0.969 | Probably Damaging | 0.875 | Possibly Damaging | 3.36 | Benign | 0.13 | Tolerated | 0.1321 | 0.2547 | 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 | 0.71 | Ambiguous | 0.1 | 0.87 | Ambiguous | 0.79 | Ambiguous | 0.65 | Ambiguous | 0.233 | Likely Benign | -2.76 | Deleterious | 0.998 | Probably Damaging | 0.964 | Probably Damaging | 3.41 | Benign | 0.15 | Tolerated | 0.1191 | 0.1276 | 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 | 3.68 | Destabilizing | 0.2 | 8.43 | Destabilizing | 6.06 | Destabilizing | 0.82 | Ambiguous | 0.469 | Likely Benign | -5.66 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.34 | Benign | 0.07 | Tolerated | 3.37 | 34 | 0.2256 | 0.3631 | -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 | 0.21 | Likely Benign | 0.1 | 0.12 | Likely Benign | 0.17 | Likely Benign | 0.33 | Likely Benign | 0.295 | Likely Benign | -3.69 | Deleterious | 0.980 | Probably Damaging | 0.943 | Probably Damaging | 3.37 | Benign | 0.20 | Tolerated | 0.1241 | 0.1124 | 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 | -0.88 | Ambiguous | 0.1 | -0.30 | Likely Benign | -0.59 | Ambiguous | 0.28 | Likely Benign | 0.347 | Likely Benign | -6.65 | Deleterious | 0.987 | Probably Damaging | 0.914 | Probably Damaging | 3.49 | Benign | 0.36 | Tolerated | 0.0554 | 0.4317 | -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 | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | 0.214 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 0.0987 | 0.2358 | 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 | 0.74 | Ambiguous | 0.1 | 0.39 | Likely Benign | 0.57 | Ambiguous | 0.32 | Likely Benign | 0.214 | Likely Benign | -4.07 | Deleterious | 0.996 | Probably Damaging | 0.974 | Probably Damaging | 3.37 | Benign | 0.19 | Tolerated | 0.0987 | 0.2358 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1960G>A | E654K 2D AIThe SynGAP1 missense variant E654K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, Foldetta predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Overall, the majority of high‑confidence predictions lean toward pathogenicity, and the variant is not contradicted by any ClinVar annotation. Thus, based on the available computational evidence, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -12.587 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.12 | Likely Benign | 0.3 | 0.53 | Ambiguous | 0.33 | Likely Benign | -0.17 | Likely Benign | 0.435 | Likely Benign | -3.80 | Deleterious | 0.921 | Possibly Damaging | 0.303 | Benign | 3.44 | Benign | 0.11 | Tolerated | 0.2365 | 0.4224 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1960G>C | E654Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654Q 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, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, SIFT, 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 likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of tools (nine benign vs. five pathogenic) suggest the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -10.368 | Likely Pathogenic | 0.699 | Likely Pathogenic | Likely Benign | 0.00 | Likely Benign | 0.0 | 0.18 | Likely Benign | 0.09 | Likely Benign | -0.12 | Likely Benign | 0.298 | Likely Benign | -2.79 | Deleterious | 0.244 | Benign | 0.075 | Benign | 3.33 | Benign | 0.02 | Affected | 0.1140 | 0.3913 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1961A>C | E654A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E654A has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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) as Likely Pathogenic, and Foldetta as Benign. Overall, the balance of evidence favors 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 | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -10.797 | Likely Pathogenic | 0.873 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.1 | 0.20 | Likely Benign | 0.35 | Likely Benign | 0.25 | Likely Benign | 0.512 | Likely Pathogenic | -5.70 | Deleterious | 0.986 | Probably Damaging | 0.875 | Possibly Damaging | 3.34 | Benign | 0.02 | Affected | 0.3367 | 0.3971 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1961A>G | E654G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact are premPS and FATHMM, while the majority (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, 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 E654G. 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 | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -12.487 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 1.29 | Ambiguous | 0.2 | 1.62 | Ambiguous | 1.46 | Ambiguous | 0.34 | Likely Benign | 0.547 | Likely Pathogenic | -6.73 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.2818 | 0.3109 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1961A>T | E654V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654V 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, 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. FoldX and AlphaMissense‑Optimized are inconclusive. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools (8 pathogenic vs. 4 benign) and the SGM‑Consensus result 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. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -12.306 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.0 | -0.33 | Likely Benign | 0.11 | Likely Benign | 0.21 | Likely Benign | 0.540 | Likely Pathogenic | -6.66 | Deleterious | 0.988 | Probably Damaging | 0.734 | Possibly Damaging | 3.31 | Benign | 0.01 | Affected | 0.0686 | 0.4757 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1962G>C | E654D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. 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 benign. Overall, the predictions are mixed, with a slight majority leaning toward benign, but the high‑accuracy tools conflict. The variant is most likely benign based on the aggregate 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 | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -10.454 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.0 | 0.52 | Ambiguous | 0.48 | Likely Benign | 0.29 | Likely Benign | 0.166 | Likely Benign | -2.87 | Deleterious | 0.906 | Possibly Damaging | 0.429 | Benign | 3.38 | Benign | 0.11 | Tolerated | 0.1678 | 0.2583 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1962G>T | E654D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E654D has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are SGM Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain (treated as unavailable), SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. No other folding‑stability results are available. Overall, the balance of evidence leans toward a benign interpretation, and this assessment does not contradict 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 | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -10.454 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.0 | 0.52 | Ambiguous | 0.48 | Likely Benign | 0.29 | Likely Benign | 0.166 | Likely Benign | -2.87 | Deleterious | 0.906 | Possibly Damaging | 0.429 | Benign | 3.38 | Benign | 0.11 | Tolerated | 0.1678 | 0.2583 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1936C>A | L646M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, 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, while Foldetta’s stability analysis remains uncertain. Overall, the evidence overwhelmingly supports a benign classification for this variant, 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 Benign | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -1.911 | Likely Benign | 0.152 | Likely Benign | Likely Benign | 0.70 | Ambiguous | 0.1 | 1.66 | Ambiguous | 1.18 | Ambiguous | -1.10 | Stabilizing | 0.106 | Likely Benign | 1.86 | Neutral | 0.211 | Benign | 0.055 | Benign | 3.57 | Benign | 1.00 | Tolerated | 0.2041 | 0.3427 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1936C>G | L646V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM, whereas pathogenic predictions arise from FoldX, Rosetta, premPS, SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs 1 pathogenic votes). High‑accuracy assessments further indicate AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools, including the high‑accuracy methods, lean toward a benign 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 Benign | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -8.995 | Likely Pathogenic | 0.332 | Likely Benign | Likely Benign | 3.82 | Destabilizing | 0.2 | 2.01 | Destabilizing | 2.92 | Destabilizing | 1.41 | Destabilizing | 0.125 | Likely Benign | -1.40 | Neutral | 0.040 | Benign | 0.021 | Benign | 3.21 | Benign | 0.03 | Affected | 0.2200 | 0.3767 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1937T>A | L646Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L646Q lies 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, FATHMM, and AlphaMissense‑Optimized. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Taken together, the overwhelming majority of evidence indicates that 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 | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.735 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 3.23 | Destabilizing | 0.1 | 3.04 | Destabilizing | 3.14 | Destabilizing | 2.12 | Destabilizing | 0.462 | Likely Benign | -2.78 | Deleterious | 0.994 | Probably Damaging | 0.790 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.2090 | 0.1963 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1937T>C | L646P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646P 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 | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.956 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 7.34 | Destabilizing | 0.5 | 12.08 | Destabilizing | 9.71 | Destabilizing | 2.72 | Destabilizing | 0.604 | Likely Pathogenic | -4.55 | Deleterious | 0.999 | Probably Damaging | 0.926 | Probably Damaging | 3.17 | Benign | 0.00 | Affected | 0.3481 | 0.1874 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1937T>G | L646R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L646R 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, and FATHMM, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, 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 further support a deleterious effect: AlphaMissense‑Optimized is uncertain, SGM Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the preponderance of evidence points to a pathogenic effect for L646R, 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 | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.393 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 4.44 | Destabilizing | 0.2 | 3.94 | Destabilizing | 4.19 | Destabilizing | 2.75 | Destabilizing | 0.455 | Likely Benign | -3.56 | Deleterious | 0.014 | Benign | 0.002 | Benign | 3.17 | Benign | 0.03 | Affected | 0.2304 | 0.1405 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| 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 | 0.13 | Likely Benign | 0.2 | -0.01 | Likely Benign | 0.06 | Likely Benign | 0.91 | Ambiguous | 0.269 | Likely Benign | -3.07 | Deleterious | 0.945 | Possibly Damaging | 0.918 | Probably Damaging | -1.37 | Pathogenic | 0.46 | Tolerated | 0.3104 | 0.0780 | 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 | 0.63 | Ambiguous | 0.4 | 0.78 | Ambiguous | 0.71 | Ambiguous | 1.06 | Destabilizing | 0.386 | Likely Benign | -3.40 | Deleterious | 0.924 | Possibly Damaging | 0.674 | Possibly Damaging | -1.25 | Pathogenic | 0.21 | Tolerated | 0.2583 | 0.0650 | 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 | 0.12 | Likely Benign | 0.3 | -0.85 | Ambiguous | -0.37 | Likely Benign | 0.84 | Ambiguous | 0.498 | Likely Benign | -5.36 | Deleterious | 0.961 | Probably Damaging | 0.990 | Probably Damaging | -1.44 | Pathogenic | 0.10 | Tolerated | 0.1482 | 0.2619 | 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 | 0.13 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.32 | Likely Benign | 0.94 | Ambiguous | 0.238 | Likely Benign | -2.16 | Neutral | 0.002 | Benign | 0.015 | Benign | -1.41 | Pathogenic | 0.11 | Tolerated | 3.37 | 35 | 0.3363 | 0.0647 | 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 | -0.04 | Likely Benign | 0.3 | -0.36 | Likely Benign | -0.20 | Likely Benign | 0.40 | Likely Benign | 0.491 | Likely Benign | -7.35 | Deleterious | 0.996 | Probably Damaging | 0.993 | Probably Damaging | -1.49 | Pathogenic | 0.02 | Affected | 0.0769 | 0.2713 | -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 | 0.26 | Likely Benign | 0.2 | 0.57 | Ambiguous | 0.42 | Likely Benign | 1.00 | Destabilizing | 0.430 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.922 | Probably Damaging | -1.44 | Pathogenic | 0.07 | Tolerated | 0.2470 | 0.0926 | 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 | 0.26 | Likely Benign | 0.2 | 0.57 | Ambiguous | 0.42 | Likely Benign | 1.00 | Destabilizing | 0.430 | Likely Benign | -4.37 | Deleterious | 0.993 | Probably Damaging | 0.922 | Probably Damaging | -1.44 | Pathogenic | 0.07 | Tolerated | 0.2470 | 0.0926 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| 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 | 0.10 | Likely Benign | 0.1 | 1.19 | Ambiguous | 0.65 | Ambiguous | 0.40 | Likely Benign | 0.217 | Likely Benign | -4.37 | Deleterious | 0.880 | Possibly Damaging | 0.430 | Benign | 3.33 | Benign | 0.10 | Tolerated | 0.1152 | 0.5531 | 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 | 0.20 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.53 | Ambiguous | 0.57 | Ambiguous | 0.356 | Likely Benign | -5.96 | Deleterious | 0.996 | Probably Damaging | 0.852 | Possibly Damaging | 3.35 | Benign | 0.11 | Tolerated | 0.1341 | 0.6156 | 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 | -0.14 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.32 | Likely Benign | 0.07 | Likely Benign | 0.399 | Likely Benign | -7.95 | Deleterious | 0.998 | Probably Damaging | 0.904 | Possibly Damaging | 3.35 | Benign | 0.14 | Tolerated | 0.0540 | 0.6213 | -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 | -0.04 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.46 | Likely Benign | 0.43 | Likely Benign | 0.425 | Likely Benign | -6.96 | Deleterious | 0.978 | Probably Damaging | 0.602 | Possibly Damaging | 3.33 | Benign | 0.29 | Tolerated | 0.3591 | 0.5169 | 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 | 0.66 | Ambiguous | 0.1 | 1.93 | Ambiguous | 1.30 | Ambiguous | 0.54 | Ambiguous | 0.422 | Likely Benign | -6.36 | Deleterious | 0.994 | Probably Damaging | 0.824 | Possibly Damaging | 3.32 | Benign | 0.09 | Tolerated | 0.3751 | 0.4898 | 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 | 0.23 | Likely Benign | 0.1 | 0.98 | Ambiguous | 0.61 | Ambiguous | 0.33 | Likely Benign | 0.521 | Likely Pathogenic | -7.95 | Deleterious | 0.973 | Probably Damaging | 0.658 | Possibly Damaging | 3.31 | Benign | 0.09 | Tolerated | 0.0713 | 0.5526 | -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 | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | 0.162 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 0.1330 | 0.5177 | 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 | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | 0.162 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 0.1330 | 0.5177 | 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 | 1.35 | Ambiguous | 0.0 | -3.46 | Stabilizing | -1.06 | Ambiguous | 0.54 | Ambiguous | 0.305 | Likely Benign | -6.67 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0.1659 | 0.5782 | 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 | 1.23 | Ambiguous | 0.0 | -3.14 | Stabilizing | -0.96 | Ambiguous | 0.50 | Likely Benign | 0.266 | Likely Benign | -6.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 0.3489 | 0.4775 | 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 | 1.14 | Ambiguous | 0.0 | -3.31 | Stabilizing | -1.09 | Ambiguous | 0.60 | Ambiguous | 0.226 | Likely Benign | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.49 | Benign | 0.01 | Affected | 3.38 | 26 | 0.3548 | 0.4843 | -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 | 1.19 | Ambiguous | 0.0 | -3.28 | Stabilizing | -1.05 | Ambiguous | 0.31 | Likely Benign | 0.343 | Likely Benign | -7.75 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.44 | Benign | 0.01 | Affected | 0.1819 | 0.4328 | 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 | 0.34 | Likely Benign | 0.1 | -3.52 | Stabilizing | -1.59 | Ambiguous | 0.61 | Ambiguous | 0.461 | Likely Benign | -7.72 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.51 | Benign | 0.03 | Affected | 0.1448 | 0.2846 | 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 | 1.10 | Ambiguous | 0.0 | -3.52 | Stabilizing | -1.21 | Ambiguous | 0.35 | Likely Benign | 0.324 | Likely Benign | -8.48 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.67 | Benign | 0.04 | Affected | 0.2228 | 0.6354 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| 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 | 0.50 | Ambiguous | 0.2 | 0.98 | Ambiguous | 0.74 | Ambiguous | 0.81 | Ambiguous | 0.233 | Likely Benign | -3.35 | Deleterious | 0.996 | Probably Damaging | 0.973 | Probably Damaging | 3.40 | Benign | 0.06 | Tolerated | 0.0943 | 0.5902 | 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 | 2.75 | Destabilizing | 0.3 | 8.32 | Destabilizing | 5.54 | Destabilizing | 0.72 | Ambiguous | 0.459 | Likely Benign | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1494 | 0.4309 | 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 | 0.81 | Ambiguous | 0.0 | 1.35 | Ambiguous | 1.08 | Ambiguous | 0.69 | Ambiguous | 0.268 | Likely Benign | -2.70 | Deleterious | 0.965 | Probably Damaging | 0.972 | Probably Damaging | 3.47 | Benign | 0.10 | Tolerated | 0.2003 | 0.4322 | 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 | 3.86 | Destabilizing | 0.2 | 5.23 | Destabilizing | 4.55 | Destabilizing | 1.59 | Destabilizing | 0.653 | Likely Pathogenic | -4.67 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.38 | Benign | 0.07 | Tolerated | 3.37 | 32 | 0.0823 | 0.1695 | 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 | 1.79 | Ambiguous | 0.0 | 2.29 | Destabilizing | 2.04 | Destabilizing | 1.23 | Destabilizing | 0.355 | Likely Benign | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.980 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 0.1670 | 0.3078 | 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 | 0.04 | Likely Benign | 0.2 | 0.27 | Likely Benign | 0.16 | Likely Benign | 0.46 | Likely Benign | 0.306 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.955 | Probably Damaging | 3.55 | Benign | 0.04 | Affected | 3.37 | 32 | 0.0792 | 0.5638 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||
| c.691T>A | F231I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231I 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 polyPhen‑2 HumVar and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). 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, while Foldetta’s stability prediction is uncertain and thus not considered evidence. No other tools provide definitive pathogenic or benign conclusions. Based on the preponderance of pathogenic predictions and the lack of contrary evidence, the variant is most likely pathogenic; 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 | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.827 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.16 | Ambiguous | 0.4 | 1.65 | Ambiguous | 1.41 | Ambiguous | 0.94 | Ambiguous | 0.894 | Likely Pathogenic | -5.01 | Deleterious | 0.759 | Possibly Damaging | 0.328 | Benign | 5.76 | Benign | 0.00 | Affected | 0.2122 | 0.2813 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.691T>C | F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from 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 for F231L, 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 | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.482 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.3 | 1.26 | Ambiguous | 1.17 | Ambiguous | 0.85 | Ambiguous | 0.801 | Likely Pathogenic | -5.08 | Deleterious | 0.390 | Benign | 0.142 | Benign | 6.04 | Benign | 0.01 | Affected | 0.2338 | 0.3794 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.691T>G | F231V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on 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 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 status; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates pathogenicity. Taken together, the evidence overwhelmingly points to a pathogenic effect for F231V, 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 | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.201 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.3 | 2.30 | Destabilizing | 2.23 | Destabilizing | 1.13 | Destabilizing | 0.910 | Likely Pathogenic | -5.90 | Deleterious | 0.759 | Possibly Damaging | 0.328 | Benign | 5.72 | Benign | 0.00 | Affected | 0.2212 | 0.3030 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.692T>A | F231Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effects include Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy methods give AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of standard tools lean benign, but the two most accurate predictors and the consensus vote favor pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no classification for F231Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.831 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.1 | 0.00 | Likely Benign | 0.35 | Likely Benign | 0.85 | Ambiguous | 0.687 | Likely Pathogenic | -2.60 | Deleterious | 0.437 | Benign | 0.079 | Benign | 5.50 | Benign | 0.12 | Tolerated | 0.1355 | 0.2732 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.692T>C | F231S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231S 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 polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, 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, 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 any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -14.655 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.89 | Destabilizing | 0.4 | 4.22 | Destabilizing | 3.56 | Destabilizing | 2.22 | Destabilizing | 0.909 | Likely Pathogenic | -6.92 | Deleterious | 0.608 | Possibly Damaging | 0.205 | Benign | 5.48 | Benign | 0.00 | Affected | 0.4297 | 0.0544 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.692T>G | F231C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231C is not reported in ClinVar and is absent from gnomAD. 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 deleterious effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: 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 are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, 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 | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.315 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.26 | Destabilizing | 0.3 | 2.82 | Destabilizing | 2.54 | Destabilizing | 2.04 | Destabilizing | 0.937 | Likely Pathogenic | -6.89 | Deleterious | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.2527 | 0.1612 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.693T>A | F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from 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 for F231L, 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 | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.482 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.3 | 1.26 | Ambiguous | 1.17 | Ambiguous | 0.85 | Ambiguous | 0.662 | Likely Pathogenic | -5.08 | Deleterious | 0.390 | Benign | 0.142 | Benign | 6.04 | Benign | 0.01 | Affected | 0.2338 | 0.3794 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.693T>G | F231L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include polyPhen‑2 HumDiv, polyPhen‑2 HumVar and FATHMM, whereas REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized all predict a pathogenic effect. The SGM‑Consensus score is labeled Likely Pathogenic, and the remaining tools (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy methods give a pathogenic verdict from AlphaMissense‑Optimized, a Likely Pathogenic result from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain outcome from Foldetta. Overall, the majority of evidence points to a pathogenic impact for F231L, 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 | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.482 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.07 | Ambiguous | 0.3 | 1.26 | Ambiguous | 1.17 | Ambiguous | 0.85 | Ambiguous | 0.661 | Likely Pathogenic | -5.08 | Deleterious | 0.390 | Benign | 0.142 | Benign | 6.04 | Benign | 0.01 | Affected | 0.2338 | 0.3794 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.697T>A | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors pathogenicity (3 pathogenic vs 1 benign). Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic 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. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | 0.764 | Likely Pathogenic | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0.4528 | 0.2833 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.697T>C | C233R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233R 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods reinforce the pathogenic prediction: 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 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 annotation and gnomAD presence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -16.789 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.79 | Destabilizing | 3.4 | 2.17 | Destabilizing | 2.98 | Destabilizing | 1.75 | Destabilizing | 0.830 | Likely Pathogenic | -10.68 | Deleterious | 0.002 | Benign | 0.002 | Benign | 5.71 | Benign | 0.01 | Affected | 0.1733 | 0.2212 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.697T>G | C233G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233G 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 polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy predictions: AlphaMissense‑Optimized reports Pathogenic; SGM‑Consensus reports Likely Pathogenic; Foldetta is Uncertain. Overall, the majority of available predictions indicate a pathogenic impact. Therefore, 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 | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.155 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 1.29 | Ambiguous | 0.1 | 1.01 | Ambiguous | 1.15 | Ambiguous | 1.31 | Destabilizing | 0.849 | Likely Pathogenic | -10.68 | Deleterious | 0.596 | Possibly Damaging | 0.107 | Benign | 5.79 | Benign | 0.09 | Tolerated | 0.3317 | 0.3570 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.698G>A | C233Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233Y 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 Rosetta and FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, 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, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the aggregate 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 | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.893 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 13.15 | Destabilizing | 4.6 | 0.04 | Likely Benign | 6.60 | Destabilizing | 0.71 | Ambiguous | 0.904 | Likely Pathogenic | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 4.29 | 391 | 0.1324 | 0.5284 | 0 | -2 | -3.8 | 60.04 | 248.9 | -63.0 | 0.0 | 0.3 | 0.0 | 0.4 | X | X | Potentially Pathogenic | The introduced residue Tyr233 is located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Ala232) and an α helix (residues Ala236-Val250). Although the thiol group of a cysteine side chain is not a strong hydrogen bond acceptor or donor, it facilitates hydrogen bonding between Cys233 and the backbone carbonyl of Ala232 in the WT simulations. In the variant simulations, the bulky phenol ring of the Tyr233 side chain stacks with the indole ring of the Trp242 side chain. This interaction could alter the tertiary assembly of the β sheet and α helix due to the residue swap. Indeed, in the second replica simulation, the protein structure begins to unfold to accommodate the introduced Tyr233 side chain. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||
| c.698G>C | C233S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic impact for C233S, 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 | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -10.862 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.93 | Ambiguous | 1.50 | Destabilizing | 0.830 | Likely Pathogenic | -8.89 | Deleterious | 0.421 | Benign | 0.080 | Benign | 5.79 | Benign | 0.03 | Affected | 0.4528 | 0.2833 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.698G>T | C233F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, premPS, and FATHMM, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—predict a pathogenic or likely pathogenic impact. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.564 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 9.36 | Destabilizing | 3.0 | -0.19 | Likely Benign | 4.59 | Destabilizing | 0.37 | Likely Benign | 0.901 | Likely Pathogenic | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.73 | Benign | 0.00 | Affected | 0.1524 | 0.5231 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.699T>G | C233W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233W is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome, while Rosetta and premPS are uncertain. High‑accuracy assessments reinforce the pathogenic prediction: 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 stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence indicates that C233W is most likely pathogenic, 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 | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.899 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.72 | Destabilizing | 6.6 | 1.07 | Ambiguous | 7.90 | Destabilizing | 0.54 | Ambiguous | 0.772 | Likely Pathogenic | -9.79 | Deleterious | 0.983 | Probably Damaging | 0.715 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 0.1727 | 0.5292 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.694G>A | A232T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232T is listed in ClinVar as Benign (ClinVar ID 1165963.0) and is present in gnomAD (ID 6‑33435545‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. Predictions that are inconclusive are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Benign. Overall, the majority of evidence supports a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | Benign | 1 | 6-33435545-G-A | 1 | 6.20e-7 | -7.655 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | 0.47 | Likely Benign | 0.1 | -0.04 | Likely Benign | 0.22 | Likely Benign | 0.61 | Ambiguous | 0.469 | Likely Benign | -1.42 | Neutral | 0.608 | Possibly Damaging | 0.240 | Benign | 5.80 | Benign | 0.09 | Tolerated | 3.40 | 14 | 0.1621 | 0.6488 | 1 | 0 | -2.5 | 30.03 | 210.8 | -42.0 | 0.5 | 0.1 | 0.4 | 0.5 | X | Uncertain | The hydroxyl group of Thr232, located at the end of an anti-parallel β sheet strand (res. Thr228-Ala232), forms hydrogen bonds with nearby residues Glu217, Cys233, and Cys219 in the variant simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and prevent it from unfolding. The new hydrogen bond interactions may be more favorable for structural stability than the steric interactions of the methyl side chain of Ala with the side chains of Gln216 and Cys219 in the WT. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||||
| c.694G>C | A232P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232P 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, SIFT, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta remains uncertain. Overall, the majority of evaluated tools predict 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 | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -12.697 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.8 | 1.25 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | 0.748 | Likely Pathogenic | -2.75 | Deleterious | 0.917 | Possibly Damaging | 0.502 | Possibly Damaging | 5.78 | Benign | 0.06 | Tolerated | 0.2163 | 0.5259 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.694G>T | A232S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Across the evaluated in‑silico predictors, all tools except AlphaMissense‑Default converge on a benign interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict benign. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: 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. Consequently, the variant is most likely benign based on the collective predictions, 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 | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -3.264 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.23 | Likely Benign | 0.1 | -0.23 | Likely Benign | 0.00 | Likely Benign | -0.20 | Likely Benign | 0.378 | Likely Benign | 0.54 | Neutral | 0.057 | Benign | 0.025 | Benign | 5.95 | Benign | 1.00 | Tolerated | 0.2777 | 0.5300 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.695C>A | A232D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232D 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, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus. Uncertain or inconclusive results are reported for Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as pathogenic, while Foldetta remains uncertain. Overall, the majority of available predictions support a pathogenic impact. Thus, 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 | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -13.956 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.14 | Likely Benign | 0.2 | 1.55 | Ambiguous | 0.85 | Ambiguous | 0.77 | Ambiguous | 0.725 | Likely Pathogenic | -2.50 | Deleterious | 0.845 | Possibly Damaging | 0.348 | Benign | 5.78 | Benign | 0.02 | Affected | 0.2066 | 0.2896 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.695C>G | A232G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A232G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the change as benign include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Those that predict pathogenicity are polyPhen‑2 HumDiv and AlphaMissense‑Default. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance 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 | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -4.924 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.1 | 1.43 | Ambiguous | 0.93 | Ambiguous | 0.53 | Ambiguous | 0.453 | Likely Benign | -1.39 | Neutral | 0.608 | Possibly Damaging | 0.172 | Benign | 5.81 | Benign | 0.11 | Tolerated | 0.2012 | 0.4724 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.695C>T | A232V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A232V is catalogued in gnomAD (ID 6‑33435546‑C‑T) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas pathogenic calls are reported by REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and the Foldetta stability assessment predicts benign. premPS is inconclusive and therefore not considered. Overall, the majority of independent predictors lean toward pathogenicity, but the stability‑based Foldetta suggests a benign effect. With no ClinVar classification to contradict, the variant is most likely pathogenic according to the prevailing computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | 6-33435546-C-T | 2 | 1.24e-6 | -9.418 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.32 | Likely Benign | 0.55 | Ambiguous | 0.539 | Likely Pathogenic | -2.99 | Deleterious | 0.608 | Possibly Damaging | 0.240 | Benign | 5.85 | Benign | 0.06 | Tolerated | 3.40 | 14 | 0.1202 | 0.6027 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||
| c.688T>A | C230S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230S 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. With an equal split of 7 benign versus 7 pathogenic predictions overall, the higher‑confidence tools lean toward pathogenicity. Therefore, the variant is most likely pathogenic based on the available 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 | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -9.994 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.05 | Likely Benign | 0.24 | Likely Benign | 1.08 | Destabilizing | 0.859 | Likely Pathogenic | -8.24 | Deleterious | 0.421 | Benign | 0.115 | Benign | 5.91 | Benign | 0.07 | Tolerated | 0.4926 | 0.1822 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.688T>C | C230R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from FoldX and FATHMM, while pathogenic predictions are made by REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for C230R, 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 | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -12.478 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | -0.48 | Likely Benign | 0.0 | -1.61 | Ambiguous | -1.05 | Ambiguous | 1.12 | Destabilizing | 0.905 | Likely Pathogenic | -9.88 | Deleterious | 0.838 | Possibly Damaging | 0.548 | Possibly Damaging | 5.91 | Benign | 0.01 | Affected | 0.1744 | 0.1637 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.688T>G | C230G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reached a consensus fall into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results from FoldX, Rosetta, Foldetta, and premPS are treated as unavailable and do not influence the overall assessment. High‑accuracy methods specifically indicate pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Pathogenic; Foldetta remains uncertain. Based on the aggregate 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 | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -10.888 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 0.86 | Ambiguous | 0.79 | Ambiguous | 0.81 | Ambiguous | 0.775 | Likely Pathogenic | -9.95 | Deleterious | 0.001 | Benign | 0.004 | Benign | 5.85 | Benign | 0.03 | Affected | 0.3313 | 0.2574 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.689G>A | C230Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Rosetta, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” and the Foldetta stability assessment 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) also predicts pathogenic; and 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 | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -8.978 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | -0.03 | Likely Benign | 0.1 | -2.24 | Stabilizing | -1.14 | Ambiguous | 0.00 | Likely Benign | 0.816 | Likely Pathogenic | -8.46 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 6.17 | Benign | 0.14 | Tolerated | 0.1159 | 0.3655 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.689G>C | C230S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C230S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools cluster into two groups: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; pathogenic calls come from REVEL, premPS, PROVEAN, 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, SGM‑Consensus as likely pathogenic, and Foldetta as benign. No prediction or stability result is missing. Overall, the predictions are evenly split between benign and pathogenic, leaving the variant’s functional impact uncertain. This uncertainty does not contradict 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 | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -9.994 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.05 | Likely Benign | 0.24 | Likely Benign | 1.08 | Destabilizing | 0.844 | Likely Pathogenic | -8.24 | Deleterious | 0.421 | Benign | 0.115 | Benign | 5.91 | Benign | 0.07 | Tolerated | 0.4926 | 0.1822 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.689G>T | C230F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230F 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, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Foldetta and premPS give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that C230F 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 | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -11.134 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | -0.09 | Likely Benign | 0.1 | -2.03 | Stabilizing | -1.06 | Ambiguous | 0.51 | Ambiguous | 0.840 | Likely Pathogenic | -8.73 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 5.96 | Benign | 0.03 | Affected | 0.1329 | 0.4173 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.690C>G | C230W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by FATHMM and FoldX, whereas the majority of other in silico predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic outcome, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic impact for C230W, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -11.022 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.21 | Likely Benign | 0.0 | -1.87 | Ambiguous | -1.04 | Ambiguous | 0.74 | Ambiguous | 0.739 | Likely Pathogenic | -8.79 | Deleterious | 0.983 | Probably Damaging | 0.841 | Possibly Damaging | 5.84 | Benign | 0.01 | Affected | 0.1589 | 0.3663 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.835C>G | R279G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279G 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 only REVEL, which scores the variant as benign. All other evaluated tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote) which labels it “Likely Pathogenic.” AlphaMissense‑Optimized is uncertain, providing no definitive evidence. High‑accuracy assessments further support pathogenicity: the SGM‑Consensus remains “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, 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 claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | -9.941 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 3.10 | Destabilizing | 0.7 | 2.85 | Destabilizing | 2.98 | Destabilizing | 1.11 | Destabilizing | 0.442 | Likely Benign | -5.37 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.92 | Pathogenic | 0.02 | Affected | 0.2961 | 0.2209 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.835C>T | R279W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279W is listed in ClinVar with an uncertain significance (ClinVar ID 1204186.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining pathogenic‑predicating tools—FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a deleterious impact. Uncertain or inconclusive results 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 pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for R279W, 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 | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | Uncertain | 1 | -11.417 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 2.00 | Destabilizing | 0.8 | 1.47 | Ambiguous | 1.74 | Ambiguous | 0.80 | Ambiguous | 0.485 | Likely Benign | -6.29 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.00 | Affected | 3.39 | 18 | 0.1200 | 0.2519 | 2 | -3 | 3.6 | 30.03 | 270.0 | 38.3 | 0.1 | 0.0 | 0.3 | 0.0 | Uncertain | The guanidinium group of Arg279, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), can form hydrogen bond with the backbone carbonyl groups of nearby loop residues (e.g., Ser296, Ser331, and As332) and form salt bridges with the carboxylate groups of Asp330 and Asp332. In the WT simulations, Arg279 sporadically forms a salt bridge even with the carboxylate group of Glu613, loosely connecting the C2 domain and GAP domain. Meanwhile, the indole ring of the Trp279 side chain is unable to hydrogen bond with the loop residues in the variant simulations. The lack of hydrogen bond or salt bridge formation with the loop residues could be significant, as Arg279 and the loops face the polar head group region of the membrane. Thus, although Trp279 could interact with the membrane surface as a “lipid anchor,” any changes to the wider loop dynamics could still adversely affect the formation of a stable SynGAP-membrane association. However, no definite conclusions on the effect of the residue swap on the SynGAP-membrane association can be drawn from solvent-only simulations. | |||||||||||||||||
| c.836G>A | R279Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279Q is reported in gnomAD (ID 6‑33437741‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect are SIFT and AlphaMissense‑Optimized; those that agree on a pathogenic effect are SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of reliable predictors (nine pathogenic vs two benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and 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 | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | 6-33437741-G-A | 6 | 3.72e-6 | -8.730 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 1.37 | Ambiguous | 0.1 | 0.88 | Ambiguous | 1.13 | Ambiguous | 1.35 | Destabilizing | 0.554 | Likely Pathogenic | -2.61 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.06 | Tolerated | 3.39 | 18 | 0.2680 | 0.1792 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||
| c.836G>C | R279P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign effect. FoldX reports an uncertain outcome, but Rosetta, Foldetta, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all predict pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, based on a majority vote of the aforementioned predictors, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, 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 | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | -14.926 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.42 | Ambiguous | 0.9 | 4.27 | Destabilizing | 2.85 | Destabilizing | 1.21 | Destabilizing | 0.626 | Likely Pathogenic | -5.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.02 | Affected | 0.2179 | 0.3281 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.836G>T | R279L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R279L is reported in gnomAD (ID 6‑33437741‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a unanimous majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | 6-33437741-G-T | 1 | 6.20e-7 | -12.390 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.01 | Likely Benign | 0.2 | 0.14 | Likely Benign | 0.08 | Likely Benign | 0.39 | Likely Benign | 0.576 | Likely Pathogenic | -5.37 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.91 | Pathogenic | 0.03 | Affected | 3.39 | 18 | 0.1682 | 0.3266 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||
| c.793A>C | K265Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K265Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Among standard in‑silico predictors, five tools (REVEL, FoldX, PROVEAN, AlphaMissense‑Optimized, Foldetta) predict a benign effect, while five (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM) predict pathogenicity. Three tools (premPS, AlphaMissense‑Default, Rosetta) are inconclusive. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign outcome from Foldetta. Overall, the predictions are mixed; the balance of evidence, including the two high‑confidence benign calls, suggests the variant is more likely benign, and this does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.533 | Likely Pathogenic | 0.505 | Ambiguous | Likely Benign | 0.35 | Likely Benign | 0.1 | -1.15 | Ambiguous | -0.40 | Likely Benign | 0.80 | Ambiguous | 0.386 | Likely Benign | -2.46 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.85 | Pathogenic | 0.05 | Affected | 0.4401 | 0.1062 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.793A>G | K265E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265E missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and Foldetta. Those that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are AlphaMissense‑Optimized, FoldX, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evaluated tools (eight pathogenic vs. three benign) indicate a pathogenic effect. Thus, 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 | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -12.163 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.63 | Ambiguous | 0.2 | 0.00 | Likely Benign | 0.32 | Likely Benign | 0.95 | Ambiguous | 0.461 | Likely Benign | -2.79 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.94 | Pathogenic | 0.05 | Affected | 0.3801 | 0.0882 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.794A>C | K265T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265T missense variant is reported in gnomAD (ID 6‑33437699‑A‑C) but has no ClinVar entry. Prediction tools that classify the variant as benign include REVEL, SIFT, and Rosetta. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools give uncertain results: FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. 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 evidence points to a pathogenic effect. This conclusion is not contradicted by 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 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | 6-33437699-A-C | 1 | 6.20e-7 | -9.425 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.68 | Ambiguous | 0.83 | Ambiguous | 0.441 | Likely Benign | -3.75 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.07 | Tolerated | 3.38 | 18 | 0.2042 | 0.3178 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||||||
| c.794A>G | K265R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K265R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. 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 reports benign. No prediction or stability result is missing or inconclusive. Based on the aggregate evidence, the variant is most likely benign, 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 Benign | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -3.366 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.04 | Likely Benign | 0.1 | -0.44 | Likely Benign | -0.20 | Likely Benign | 0.30 | Likely Benign | 0.223 | Likely Benign | -1.08 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.90 | Pathogenic | 0.36 | Tolerated | 0.4713 | 0.0976 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.794A>T | K265M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265M missense variant is not reported in ClinVar and has no entries in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify it as damaging. Benign predictions are limited to FoldX, Foldetta, and premPS. Uncertain results come from Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments reinforce this view: the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, while Foldetta predicts a benign folding‑stability change. Overall, the preponderance of evidence supports a pathogenic classification for K265M, 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 | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -10.885 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | -0.22 | Likely Benign | 0.2 | -0.63 | Ambiguous | -0.43 | Likely Benign | 0.19 | Likely Benign | 0.516 | Likely Pathogenic | -3.78 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.79 | Pathogenic | 0.01 | Affected | 0.1005 | 0.3695 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.795G>C | K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, whereas the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain results are reported by FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available 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 | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.759 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.57 | Ambiguous | 0.85 | Ambiguous | 0.350 | Likely Benign | -3.26 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.86 | Pathogenic | 0.03 | Affected | 0.3691 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.795G>T | K265N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and Rosetta, while the majority of algorithms predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results are reported only for FoldX, Foldetta, and premPS, and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -8.759 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.98 | Ambiguous | 0.1 | 0.16 | Likely Benign | 0.57 | Ambiguous | 0.85 | Ambiguous | 0.351 | Likely Benign | -3.26 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.86 | Pathogenic | 0.03 | Affected | 0.3691 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.832A>C | K278Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 a likely pathogenic outcome, whereas Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts a benign effect, and AlphaMissense‑Optimized remains uncertain. Overall, the majority of evidence points to a pathogenic impact for K278Q, 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 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -11.107 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.1 | 0.25 | Likely Benign | 0.24 | Likely Benign | 0.73 | Ambiguous | 0.387 | Likely Benign | -3.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.71 | Pathogenic | 0.05 | Affected | 0.3770 | 0.0672 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.832A>G | K278E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278E 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, and SIFT, all of which score the substitution as tolerated. In contrast, a majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic verdict. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, predicts a benign effect. premPS is inconclusive and therefore not considered evidence. High‑accuracy assessments therefore show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as pathogenic, and Foldetta as benign. Overall, the preponderance of evidence from multiple independent predictors indicates that K278E 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 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -14.047 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.40 | Likely Benign | 0.68 | Ambiguous | 0.463 | Likely Benign | -3.64 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.76 | Pathogenic | 0.06 | Tolerated | 0.3189 | 0.0492 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.833A>C | K278T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278T is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict any ClinVar annotation because the variant is not yet classified in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -11.227 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.85 | Ambiguous | 0.2 | -0.08 | Likely Benign | 0.39 | Likely Benign | 0.46 | Likely Benign | 0.484 | Likely Benign | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.70 | Pathogenic | 0.04 | Affected | 0.1775 | 0.2220 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.833A>G | K278R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278R 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact. Thus, 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. | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -5.313 | Likely Benign | 0.216 | Likely Benign | Likely Benign | -0.05 | Likely Benign | 0.0 | 0.18 | Likely Benign | 0.07 | Likely Benign | 0.13 | Likely Benign | 0.282 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.73 | Pathogenic | 0.10 | Tolerated | 0.3926 | 0.0489 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.833A>T | K278M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278M is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Foldetta, and premPS, whereas the majority of tools predict a pathogenic effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, 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 pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic impact for K278M, 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 | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -12.861 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | -0.15 | Likely Benign | 0.1 | -0.59 | Ambiguous | -0.37 | Likely Benign | 0.25 | Likely Benign | 0.526 | Likely Pathogenic | -5.47 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.67 | Pathogenic | 0.01 | Affected | 0.0975 | 0.2584 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.834G>C | K278N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278N is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give mixed 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) predicts benign. Overall, the majority of tools support a pathogenic effect, so the variant is most likely pathogenic; this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -10.611 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.23 | Likely Benign | 0.44 | Likely Benign | 0.255 | Likely Benign | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.81 | Pathogenic | 0.07 | Tolerated | 0.3071 | 0.0568 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.834G>T | K278N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K278N is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas tools that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further 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. With a majority of evidence pointing to deleterious effects 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. | Likely Pathogenic | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -10.611 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.23 | Likely Benign | 0.44 | Likely Benign | 0.255 | Likely Benign | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.81 | Pathogenic | 0.07 | Tolerated | 0.3071 | 0.0568 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| 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 | 0.88 | Ambiguous | 0.0 | 1.27 | Ambiguous | 1.08 | Ambiguous | 0.59 | Ambiguous | 0.147 | Likely Benign | -1.64 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.11 | Tolerated | 0.0606 | 0.3362 | 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 | 2.89 | Destabilizing | 0.1 | 2.38 | Destabilizing | 2.64 | Destabilizing | 1.41 | Destabilizing | 0.276 | Likely Benign | -2.83 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.29 | Benign | 0.02 | Affected | 0.1149 | 0.3056 | 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 | 2.84 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.13 | Destabilizing | 2.24 | Destabilizing | 0.655 | Likely Pathogenic | -5.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.0871 | 0.0958 | -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 | 7.45 | Destabilizing | 0.2 | 11.99 | Destabilizing | 9.72 | Destabilizing | 2.19 | Destabilizing | 0.695 | Likely Pathogenic | -6.72 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.3211 | 0.1221 | -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 | 6.36 | Destabilizing | 0.2 | 4.96 | Destabilizing | 5.66 | Destabilizing | 2.08 | Destabilizing | 0.648 | Likely Pathogenic | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.24 | Benign | 0.00 | Affected | 0.1126 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.685A>C | K229Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, FATHMM, and Foldetta; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment does not conflict with ClinVar status, which currently has no entry for K229Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -9.606 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.41 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.18 | Likely Benign | 0.55 | Ambiguous | 0.813 | Likely Pathogenic | -3.03 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 0.4456 | 0.1057 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.685A>G | K229E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K229E is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that classify the variant as benign include FoldX, Rosetta, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, 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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall distribution of predictions, the variant is most likely pathogenic; this conclusion does not contradict the ClinVar status, which currently has no entry for K229E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -12.828 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.0 | 0.24 | Likely Benign | 0.36 | Likely Benign | 0.18 | Likely Benign | 0.816 | Likely Pathogenic | -3.10 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.84 | Benign | 0.09 | Tolerated | 0.3915 | 0.0793 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.686A>C | K229T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K229T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include Rosetta, Foldetta, premPS, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy methods give a pathogenic result from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and a benign outcome from Foldetta. Overall, the majority of evidence points to a pathogenic effect, 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 | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -12.639 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.83 | Ambiguous | 0.0 | -0.08 | Likely Benign | 0.38 | Likely Benign | 0.00 | Likely Benign | 0.813 | Likely Pathogenic | -4.77 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.86 | Benign | 0.01 | Affected | 0.1890 | 0.3029 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.686A>G | K229R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229R missense variant is catalogued in gnomAD (ID 6‑33435537‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a benign effect: FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. In contrast, REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar predict pathogenic. AlphaMissense‑Default is uncertain and is treated as unavailable. The high‑accuracy consensus methods reinforce the benign assessment: 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. Overall, the majority of evidence supports a benign classification, and this 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 | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | 6-33435537-A-G | 1 | 6.20e-7 | -5.651 | Likely Benign | 0.437 | Ambiguous | Likely Benign | 0.09 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.06 | Likely Benign | 0.40 | Likely Benign | 0.628 | Likely Pathogenic | -2.00 | Neutral | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.84 | Benign | 0.19 | Tolerated | 3.43 | 12 | 0.4921 | 0.0972 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||||
| c.686A>T | K229I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from FoldX, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, REVEL, 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports benign. No prediction is inconclusive. Overall, the majority of tools, including the high‑accuracy ones, lean toward pathogenicity, and this 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 | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -15.276 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.03 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.33 | Likely Benign | -0.19 | Likely Benign | 0.833 | Likely Pathogenic | -6.52 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.92 | Benign | 0.00 | Affected | 0.1202 | 0.3711 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.687A>C | K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N 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 are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. 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 | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -13.620 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.82 | Ambiguous | 0.1 | 0.64 | Ambiguous | 0.73 | Ambiguous | 0.61 | Ambiguous | 0.590 | Likely Pathogenic | -3.79 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 0.3682 | 0.1013 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.687A>T | K229N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229N 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 include only FATHMM, whereas the remaining nine tools—REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain and therefore not considered evidence for or against pathogenicity. Based on the collective 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 | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -13.620 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.82 | Ambiguous | 0.1 | 0.64 | Ambiguous | 0.73 | Ambiguous | 0.61 | Ambiguous | 0.588 | Likely Pathogenic | -3.79 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.83 | Benign | 0.01 | Affected | 0.3682 | 0.1013 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.700C>G | R234G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234G 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 polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that agree on a pathogenic effect are REVEL, PROVEAN, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of individual predictors lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Therefore, 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. | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -7.163 | In-Between | 0.923 | Likely Pathogenic | Ambiguous | 1.50 | Ambiguous | 0.2 | 0.88 | Ambiguous | 1.19 | Ambiguous | 0.61 | Ambiguous | 0.724 | Likely Pathogenic | -4.31 | Deleterious | 0.276 | Benign | 0.103 | Benign | 5.82 | Benign | 0.12 | Tolerated | 0.3194 | 0.3426 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
| c.700C>T | R234W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234W missense variant is listed in ClinVar (ID 856396.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33435551‑C‑T). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) indicate a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as “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, is “Uncertain.” Overall, the preponderance of evidence points to a pathogenic effect, which is consistent with the ClinVar designation of uncertainty rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | Uncertain | 1 | 6-33435551-C-T | 3 | 1.86e-6 | -12.625 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.96 | Ambiguous | 0.3 | 0.69 | Ambiguous | 0.83 | Ambiguous | 0.13 | Likely Benign | 0.805 | Likely Pathogenic | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 5.76 | Benign | 0.01 | Affected | 3.40 | 14 | 0.1302 | 0.4035 | 2 | -3 | 3.6 | 30.03 | 262.8 | 39.6 | -0.1 | 0.0 | -0.2 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg234, located in a β-α loop between an anti-parallel β sheet strand (residues Gly227-Phe231) and an α helix (res. Ala236-Val250), forms a salt bridge with the carboxylate group of Glu238 in the α helix. Occasionally, it also bonds with the GAP domain residues Ser678 and Glu680. Thus, the positively charged Arg234 could contribute to the tertiary structure assembly between the PH and GAP domains. In contrast, the indole side chain of Trp234 in the variant is located on the protein surface in the variant simulations and is unable to form any interactions. | |||||||||||||
| c.701G>A | R234Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234Q missense variant is not reported in ClinVar (ClinVar ID = None) but is present in gnomAD (ID = 6‑33435552‑G‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default; premPS is uncertain and treated as unavailable. 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 evidence points to a benign effect. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | 6-33435552-G-A | 8 | 4.96e-6 | -9.675 | Likely Pathogenic | 0.666 | Likely Pathogenic | Likely Benign | 0.21 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.24 | Likely Benign | 0.57 | Ambiguous | 0.627 | Likely Pathogenic | -2.32 | Neutral | 0.892 | Possibly Damaging | 0.213 | Benign | 5.81 | Benign | 0.11 | Tolerated | 3.40 | 14 | 0.3256 | 0.2520 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||
| c.701G>C | R234P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R234P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of evaluated algorithms (REVEL, 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 assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Based on the collective evidence, 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 | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -10.126 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 1.33 | Ambiguous | 0.6 | 1.36 | Ambiguous | 1.35 | Ambiguous | 0.13 | Likely Benign | 0.826 | Likely Pathogenic | -4.43 | Deleterious | 0.929 | Possibly Damaging | 0.519 | Possibly Damaging | 5.93 | Benign | 0.04 | Affected | 0.1972 | 0.4336 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.701G>T | R234L 2D AIThe SynGAP1 missense variant R234L 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, polyPhen‑2 HumVar, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (7 pathogenic vs. 4 benign) and the pathogenic consensus from the high‑accuracy SGM‑Consensus suggest that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -11.153 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.38 | Ambiguous | 0.9 | 0.50 | Ambiguous | 0.94 | Ambiguous | 0.20 | Likely Benign | 0.734 | Likely Pathogenic | -4.64 | Deleterious | 0.649 | Possibly Damaging | 0.199 | Benign | 5.78 | Benign | 0.11 | Tolerated | 0.1846 | 0.4783 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| 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 | 0.57 | Ambiguous | 0.1 | 1.36 | Ambiguous | 0.97 | Ambiguous | 0.80 | Ambiguous | 0.246 | Likely Benign | -1.98 | Neutral | 0.908 | Possibly Damaging | 0.943 | Probably Damaging | 3.51 | Benign | 0.26 | Tolerated | 0.0653 | 0.2857 | 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 | 1.47 | Ambiguous | 0.0 | 1.36 | Ambiguous | 1.42 | Ambiguous | 0.69 | Ambiguous | 0.132 | Likely Benign | -0.79 | Neutral | 0.935 | Possibly Damaging | 0.858 | Possibly Damaging | 3.40 | Benign | 0.18 | Tolerated | 0.0833 | 0.2959 | 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 | 4.15 | Destabilizing | 0.7 | 2.96 | Destabilizing | 3.56 | Destabilizing | 0.70 | Ambiguous | 0.464 | Likely Benign | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.0422 | 0.2560 | 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 | 4.24 | Destabilizing | 0.1 | 3.56 | Destabilizing | 3.90 | Destabilizing | 2.44 | Destabilizing | 0.497 | Likely Benign | -6.82 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.25 | Benign | 0.00 | Affected | 0.0750 | 0.0412 | -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 | 3.20 | Destabilizing | 0.0 | 2.83 | Destabilizing | 3.02 | Destabilizing | 2.02 | Destabilizing | 0.502 | Likely Pathogenic | -4.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.0877 | 0.0708 | 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 | 4.50 | Destabilizing | 0.1 | 4.45 | Destabilizing | 4.48 | Destabilizing | 2.20 | Destabilizing | 0.574 | Likely Pathogenic | -5.83 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.2116 | 0.0800 | -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 | 1.06 | Ambiguous | 0.1 | 2.32 | Destabilizing | 1.69 | Ambiguous | 1.08 | Destabilizing | 0.292 | Likely Benign | -2.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.0566 | 0.2524 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| 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 | 4.77 | Destabilizing | 0.2 | 4.35 | Destabilizing | 4.56 | Destabilizing | 1.23 | Destabilizing | 0.539 | Likely Pathogenic | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1439 | 0.2002 | 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 | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | 0.435 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 0.1664 | 0.2883 | 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 | 3.61 | Destabilizing | 0.1 | 2.89 | Destabilizing | 3.25 | Destabilizing | 1.40 | Destabilizing | 0.592 | Likely Pathogenic | -6.96 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 3.36 | Benign | 0.04 | Affected | 3.37 | 34 | 0.1587 | 0.2219 | -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 | 1.35 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.80 | Ambiguous | 1.31 | Destabilizing | 0.387 | Likely Benign | -2.98 | Deleterious | 0.979 | Probably Damaging | 0.953 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.1081 | 0.1523 | 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 | 4.84 | Destabilizing | 0.0 | 4.90 | Destabilizing | 4.87 | Destabilizing | 2.52 | Destabilizing | 0.748 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.27 | Benign | 0.00 | Affected | 0.3700 | 0.0358 | -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 | 4.18 | Destabilizing | 0.0 | 4.31 | Destabilizing | 4.25 | Destabilizing | 2.20 | Destabilizing | 0.740 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.2298 | 0.1219 | -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 | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | 0.279 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 0.1664 | 0.2883 | 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 | 1.63 | Ambiguous | 0.3 | 0.95 | Ambiguous | 1.29 | Ambiguous | 1.12 | Destabilizing | 0.279 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 3.93 | Benign | 0.22 | Tolerated | 0.1664 | 0.2883 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| 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 | 1.43 | Ambiguous | 0.8 | 0.70 | Ambiguous | 1.07 | Ambiguous | 0.94 | Ambiguous | 0.284 | Likely Benign | -1.94 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.75 | Benign | 0.02 | Affected | 0.0681 | 0.2958 | 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 | 2.83 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.32 | Destabilizing | 1.39 | Destabilizing | 0.325 | Likely Benign | -2.90 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.1065 | 0.2856 | 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 | 2.91 | Destabilizing | 0.0 | 2.48 | Destabilizing | 2.70 | Destabilizing | 2.30 | Destabilizing | 0.708 | Likely Pathogenic | -5.79 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.0869 | 0.0558 | -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 | 6.92 | Destabilizing | 0.2 | 8.57 | Destabilizing | 7.75 | Destabilizing | 2.58 | Destabilizing | 0.750 | Likely Pathogenic | -6.81 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.2823 | 0.1221 | -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 | 3.32 | Destabilizing | 0.1 | 3.76 | Destabilizing | 3.54 | Destabilizing | 2.25 | Destabilizing | 0.726 | Likely Pathogenic | -5.82 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1130 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.802A>C | I268L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268L 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, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools give uncertain results: premPS 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, and Foldetta indicates a benign folding‑stability outcome. Overall, the majority of evidence points to a benign impact. 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. | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -6.544 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.1 | -0.07 | Likely Benign | 0.15 | Likely Benign | 0.96 | Ambiguous | 0.390 | Likely Benign | -1.84 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.65 | Pathogenic | 0.03 | Affected | 0.0635 | 0.3037 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.802A>G | I268V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign, while Foldetta’s stability analysis is uncertain. Overall, the majority of reliable predictors indicate a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar 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 | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -4.553 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 1.46 | Ambiguous | 0.0 | 0.95 | Ambiguous | 1.21 | Ambiguous | 0.71 | Ambiguous | 0.139 | Likely Benign | -0.56 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 2.15 | Pathogenic | 0.71 | Tolerated | 0.0845 | 0.2489 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.802A>T | I268F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; only Rosetta and Foldetta are uncertain. 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) remains uncertain. Overall, the consensus of available predictions strongly supports a pathogenic classification for I268F, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -11.426 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 2.85 | Destabilizing | 0.7 | 0.59 | Ambiguous | 1.72 | Ambiguous | 1.00 | Destabilizing | 0.685 | Likely Pathogenic | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0427 | 0.2158 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.803T>A | I268N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268N 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 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 | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -13.664 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.48 | Destabilizing | 0.1 | 3.17 | Destabilizing | 3.33 | Destabilizing | 2.21 | Destabilizing | 0.812 | Likely Pathogenic | -6.26 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.0708 | 0.0142 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.803T>C | I268T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268T is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on pathogenicity include 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 methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a destabilizing, pathogenic effect. All available predictions are concordant and point to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -10.753 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.44 | Destabilizing | 0.1 | 3.19 | Destabilizing | 3.32 | Destabilizing | 1.93 | Destabilizing | 0.828 | Likely Pathogenic | -4.24 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0882 | 0.0638 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.803T>G | I268S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268S 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 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 | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -13.032 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.93 | Destabilizing | 0.1 | 4.54 | Destabilizing | 4.74 | Destabilizing | 2.10 | Destabilizing | 0.841 | Likely Pathogenic | -5.34 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.2037 | 0.0530 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
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