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.3647T>G | L1216R 2D  AIThe SynGAP1 missense variant L1216R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus agrees. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence 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 | Coiled-coil | 0.580690 | Disordered | 0.504713 | Binding | 0.863 | 0.563 | 0.250 | -9.700 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.387 | Likely Benign | -4.39 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.16 | Pathogenic | 0.00 | Affected | 0.1071 | 0.0488 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.3779A>C | K1260T 2D  AIThe SynGAP1 missense variant K1260T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is “Likely Pathogenic” based on a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Benign predictions are limited to REVEL and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of evidence from multiple in‑silico tools indicates that K1260T 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 | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -10.099 | Likely Pathogenic | 0.772 | Likely Pathogenic | Likely Benign | 0.387 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1859 | 0.3028 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| 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.1058T>A | L353Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 L353Q missense variant has no ClinVar entry and is absent from gnomAD. Among in‑silico predictors, only REVEL classifies it as benign, whereas the majority—FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—label it pathogenic. Predictions marked uncertain include Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of pathogenic predictions outweighs the single benign call, and no ClinVar record contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -7.074 | In-Between | 0.884 | Likely Pathogenic | Ambiguous | 2.38 | Destabilizing | 0.2 | 1.41 | Ambiguous | 1.90 | Ambiguous | 2.00 | Destabilizing | 0.388 | Likely Benign | -3.56 | Deleterious | 0.947 | Possibly Damaging | 0.556 | Possibly Damaging | 1.30 | Pathogenic | 0.01 | Affected | 0.1098 | 0.1303 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1120T>C | S374P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S374P is reported in gnomAD (6‑33438025‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and Rosetta; FoldX and Foldetta are inconclusive. The high‑accuracy consensus (SGM‑Consensus) is “Likely Benign,” derived from the unanimous benign calls of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. AlphaMissense‑Optimized also predicts benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. There is no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | 6-33438025-T-C | 1 | 7.85e-7 | -4.849 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.66 | Ambiguous | 0.6 | 2.22 | Destabilizing | 1.44 | Ambiguous | 0.34 | Likely Benign | 0.388 | Likely Benign | -0.89 | Neutral | 0.396 | Benign | 0.099 | Benign | 5.30 | Benign | 0.02 | Affected | 4.32 | 13 | 0.3012 | 0.6813 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||
| c.2132T>A | L711Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L711Q 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, AlphaMissense‑Optimized, SGM Consensus, and Foldetta; Rosetta is uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts Pathogenic, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. No predictions are missing or inconclusive. 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 | 0.308712 | Structured | 0.377436 | Uncertain | 0.950 | 0.364 | 0.000 | -11.792 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.93 | Destabilizing | 0.0 | 1.68 | Ambiguous | 2.31 | Destabilizing | 1.63 | Destabilizing | 0.388 | Likely Benign | -5.67 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.31 | Benign | 0.00 | Affected | 0.1041 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2770C>T | P924S 2D  AIThe SynGAP1 missense variant P924S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this residue. Overall, the preponderance of evidence points to a pathogenic effect for P924S, and this conclusion does not conflict with the current ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.521092 | Disordered | 0.971858 | Binding | 0.293 | 0.846 | 0.250 | -4.686 | Likely Benign | 0.920 | Likely Pathogenic | Ambiguous | 0.388 | Likely Benign | -5.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 0.2952 | 0.3772 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2798A>T | H933L 2D  AIThe SynGAP1 H933L 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, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -0.858 | Likely Benign | 0.470 | Ambiguous | Likely Benign | 0.388 | Likely Benign | -6.26 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.38 | Pathogenic | 0.02 | Affected | 0.1003 | 0.5749 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||||
| c.2848G>C | G950R 2D  AIThe SynGAP1 missense variant G950R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT 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 and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for G950R, 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 Benign | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -6.929 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.388 | Likely Benign | -1.10 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.26 | Pathogenic | 0.01 | Affected | 0.1009 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3809A>C | E1270A 2D  AIThe SynGAP1 missense change E1270A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL is the only score that flags the variant as benign, whereas PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect, and the SGM‑Consensus also indicates a likely pathogenic outcome. No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a pathogenic impact for E1270A, and this conclusion is consistent with the absence of a ClinVar entry (i.e., no contradictory clinical classification). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -12.081 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.388 | Likely Benign | -5.04 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.3024 | 0.5126 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.823C>T | P275S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275S is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437728‑C‑T). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for P275S, 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. | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | 6-33437728-C-T | 1 | 6.20e-7 | -7.886 | In-Between | 0.312 | Likely Benign | Likely Benign | 2.11 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.70 | Ambiguous | 0.77 | Ambiguous | 0.388 | Likely Benign | -5.24 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.78 | Pathogenic | 0.03 | Affected | 3.38 | 19 | 0.3489 | 0.3339 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.1770C>G | S590R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R 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 (AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, Rosetta, and Foldetta) all predict a pathogenic impact; FoldX is uncertain 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) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. 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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.389 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1948A>G | N650D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650D 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, and FATHMM. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Stability‑based methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the majority of available predictions support a pathogenic impact. The variant is most likely pathogenic based on the consensus of predictive tools, 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 Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -14.267 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 1.14 | Ambiguous | 0.3 | 0.61 | Ambiguous | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.389 | Likely Benign | -4.98 | Deleterious | 0.591 | Possibly Damaging | 0.185 | Benign | 2.99 | Benign | 0.03 | Affected | 0.2320 | 0.2973 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| 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.2960A>T | D987V 2D  AIThe SynGAP1 missense variant D987V is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that D987V is most likely pathogenic, and 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 | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -4.647 | Likely Benign | 0.857 | Likely Pathogenic | Ambiguous | 0.389 | Likely Benign | -4.01 | Deleterious | 0.992 | Probably Damaging | 0.913 | Probably Damaging | 2.34 | Pathogenic | 0.00 | Affected | 0.0907 | 0.7202 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3530A>G | E1177G 2D  AIThe SynGAP1 missense variant E1177G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. 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 Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. 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 existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.566503 | Binding | 0.542 | 0.705 | 0.250 | -3.948 | Likely Benign | 0.727 | Likely Pathogenic | Likely Benign | 0.389 | Likely Benign | -2.04 | Neutral | 0.012 | Benign | 0.026 | Benign | 5.45 | Benign | 0.02 | Affected | 0.2690 | 0.4094 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.398T>G | L133R 2D AIThe SynGAP1 missense variant L133R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome (3 pathogenic vs. 1 benign votes). AlphaMissense‑Optimized independently predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence supports a pathogenic classification for L133R, and this assessment 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 | 0.422041 | Structured | 0.718429 | Binding | 0.320 | 0.896 | 0.250 | -8.857 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.389 | Likely Benign | -2.57 | Deleterious | 0.002 | Benign | 0.005 | Benign | 3.55 | Benign | 0.00 | Affected | 0.1522 | 0.0479 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.1160G>T | G387V 2D  3DClick to see structure in 3D Viewer AISynGAP1 G387V is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438065-G-T). Functional prediction tools that report a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as likely benign, while the Foldetta stability assessment (combining FoldX‑MD and Rosetta) indicates a pathogenic change. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic. Overall, the majority of predictions favor a benign impact, and this consensus does not contradict the ClinVar uncertain status; thus the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | Uncertain | 1 | 6-33438065-G-T | 22 | 1.37e-5 | -6.199 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 5.13 | Destabilizing | 1.8 | 6.44 | Destabilizing | 5.79 | Destabilizing | -0.33 | Likely Benign | 0.390 | Likely Benign | -0.54 | Neutral | 0.069 | Benign | 0.077 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 3 | 0.1586 | 0.3708 | -1 | -3 | 4.6 | 42.08 | 207.7 | -68.4 | -0.7 | 0.8 | -0.5 | 0.1 | Uncertain | Gly387 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364 and res. Ala399-Ile411). The Ω loop is assumed to directly interact with the membrane, and it is observed to move arbitrarily throughout the WT solvent simulations. This loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play significant roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Val387 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. Since the effects on the Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||
| 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.1603A>C | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R is not reported in ClinVar and is present in gnomAD (ID 6‑33438846‑A‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results come from AlphaMissense‑Optimized, Foldetta, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the balance of evidence, especially the SGM Consensus, points to a pathogenic interpretation. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | 6-33438846-A-C | 3 | 1.86e-6 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.390 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||
| c.3176G>A | G1059E 2D  AIThe SynGAP1 missense variant G1059E is reported in gnomAD (variant ID 6‑33443728‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools—SIFT and ESM1b—predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | 6-33443728-G-A | 1 | 6.22e-7 | -10.459 | Likely Pathogenic | 0.297 | Likely Benign | Likely Benign | 0.390 | Likely Benign | -0.71 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.53 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1464 | 0.4069 | -2 | 0 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||
| c.3487C>T | H1163Y 2D  AIThe SynGAP1 missense variant H1163Y 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 (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign and the SGM‑Consensus also indicating a likely benign outcome; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign based on current predictive data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -4.051 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.390 | Likely Benign | -1.81 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 5.40 | Benign | 0.08 | Tolerated | 0.0845 | 0.4487 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.626T>G | V209G 2D  AIThe SynGAP1 missense variant V209G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, 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 (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a pathogenic classification; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence indicates that V209G is 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. | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -13.763 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.05 | Destabilizing | 0.5 | 3.99 | Destabilizing | 3.52 | Destabilizing | 1.27 | Destabilizing | 0.390 | Likely Benign | -5.49 | Deleterious | 0.829 | Possibly Damaging | 0.995 | Probably Damaging | 3.65 | Benign | 0.04 | Affected | 0.1600 | 0.2035 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| 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.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.1770C>A | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R 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 (AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, Rosetta, and Foldetta) all predict a pathogenic impact; FoldX is uncertain 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) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. 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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -18.228 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.69 | Ambiguous | 0.6 | 3.21 | Destabilizing | 2.45 | Destabilizing | 1.28 | Destabilizing | 0.391 | Likely Benign | -4.88 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.11 | Benign | 0.01 | Affected | 0.0983 | 0.3388 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.1885G>C | V629L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629L has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools report uncertainty: Foldetta and premPS. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta remains uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -12.785 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.06 | Likely Benign | 0.2 | 2.26 | Destabilizing | 1.16 | Ambiguous | 0.54 | Ambiguous | 0.391 | Likely Benign | -2.79 | Deleterious | 0.975 | Probably Damaging | 0.958 | Probably Damaging | 3.22 | Benign | 0.02 | Affected | 0.0805 | 0.3336 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1982A>T | Q661L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q661L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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, so it is not used as evidence. Overall, the majority of predictions support a pathogenic impact, and this is consistent with the lack of ClinVar annotation. Therefore, the variant is most likely pathogenic, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -9.003 | Likely Pathogenic | 0.613 | Likely Pathogenic | Likely Benign | -0.19 | Likely Benign | 0.1 | -1.12 | Ambiguous | -0.66 | Ambiguous | 0.36 | Likely Benign | 0.391 | Likely Benign | -5.11 | Deleterious | 0.976 | Probably Damaging | 0.567 | Possibly Damaging | 3.49 | Benign | 0.02 | Affected | 0.0834 | 0.4675 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| c.2170G>C | A724P 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A724P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: REVEL predicts a benign effect, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS [uncertain], PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a pathogenic score; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, classifies the variant as pathogenic. No tool suggests a benign outcome, and the single benign prediction (REVEL) is outweighed by the consensus of pathogenic predictions. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this mutation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -12.817 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.90 | Destabilizing | 0.3 | 6.35 | Destabilizing | 4.63 | Destabilizing | 0.52 | Ambiguous | 0.391 | Likely Benign | -3.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.04 | Pathogenic | 0.04 | Affected | 0.1642 | 0.4273 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.2785A>T | N929Y 2D  AIThe SynGAP1 missense variant N929Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL predicts benign, whereas the remaining eleven predictors—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized—predict pathogenicity. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus result is consistent with a likely pathogenic classification. Foldetta predictions are unavailable. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this assessment does not conflict with the current ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.986867 | Binding | 0.321 | 0.851 | 0.375 | -10.327 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.391 | Likely Benign | -6.02 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.45 | Pathogenic | 0.00 | Affected | 0.0656 | 0.6489 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3179G>A | G1060D 2D  AIThe SynGAP1 missense variant G1060D 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign (2 benign vs 1 pathogenic). Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion 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. | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -9.824 | Likely Pathogenic | 0.342 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -0.58 | Neutral | 0.905 | Possibly Damaging | 0.538 | Possibly Damaging | 2.63 | Benign | 0.20 | Tolerated | 0.1703 | 0.2035 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3413C>A | S1138Y 2D  AIThe SynGAP1 missense variant S1138Y is listed in ClinVar with an “Uncertain” significance and is present in gnomAD (ID 6‑33444448‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy predictions from AlphaMissense‑Optimized and the SGM Consensus both indicate a benign outcome, while Foldetta data are missing. Overall, the balance of evidence—especially from the high‑accuracy tools—suggests that the variant is most likely benign. This benign prediction does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | Uncertain | 1 | 6-33444448-C-A | 3 | 1.86e-6 | -6.610 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.391 | Likely Benign | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.41 | Benign | 0.05 | Affected | 4.32 | 4 | 0.1034 | 0.5449 | -2 | -3 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||
| c.3433A>C | N1145H 2D  AIThe SynGAP1 missense variant N1145H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Foldetta results are unavailable. Overall, the computational evidence supports a benign classification for the variant, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.974 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.391 | Likely Benign | -2.42 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.41 | Benign | 0.02 | Affected | 0.1520 | 0.7233 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||||||||||||
| c.3797T>G | L1266R 2D AISynGAP1 missense variant L1266R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM‑Consensus confirms a likely pathogenic classification. Foldetta results are unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors and high‑accuracy tools points to a pathogenic effect, with no conflict from ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | -16.676 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.391 | Likely Benign | -5.04 | Deleterious | 0.996 | Probably Damaging | 0.951 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.1063 | 0.0891 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.1127G>C | G376A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 G376A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. FoldX and Rosetta give uncertain results and are not considered evidence for either side. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. 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. | Likely Benign | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | -6.016 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 1.74 | Ambiguous | 0.3 | -0.84 | Ambiguous | 0.45 | Likely Benign | 0.00 | Likely Benign | 0.392 | Likely Benign | -0.44 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.33 | Pathogenic | 0.03 | Affected | 0.3868 | 0.4465 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1237C>G | P413A 2D  3DClick to see structure in 3D Viewer AISynGAP1 P413A is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of algorithms—FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect for P413A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.686 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.38 | Destabilizing | 0.0 | 0.79 | Ambiguous | 1.59 | Ambiguous | 0.81 | Ambiguous | 0.392 | Likely Benign | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.19 | Benign | 0.02 | Affected | 0.3350 | 0.3863 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1253A>C | K418T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K418T variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of tools (10 pathogenic vs. 5 benign) support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar record exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -11.994 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.1 | 0.55 | Ambiguous | 0.47 | Likely Benign | 0.41 | Likely Benign | 0.392 | Likely Benign | -5.36 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.37 | Benign | 0.04 | Affected | 0.1975 | 0.1894 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.2105A>T | Q702L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q702L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 balance of evidence leans toward 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 | 0.074921 | Structured | 0.397258 | Uncertain | 0.907 | 0.345 | 0.000 | -9.954 | Likely Pathogenic | 0.149 | Likely Benign | Likely Benign | -0.13 | Likely Benign | 0.0 | 0.09 | Likely Benign | -0.02 | Likely Benign | 0.16 | Likely Benign | 0.392 | Likely Benign | -5.66 | Deleterious | 0.939 | Possibly Damaging | 0.838 | Possibly Damaging | 3.42 | Benign | 0.00 | Affected | 0.0584 | 0.3628 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||
| c.2788C>G | P930A 2D AIThe SynGAP1 missense variant P930A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that P930A 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 | 0.538167 | Disordered | 0.988036 | Binding | 0.304 | 0.855 | 0.375 | -8.938 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.392 | Likely Benign | -6.03 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.68 | Pathogenic | 0.00 | Affected | 0.3376 | 0.4983 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2794T>G | F932V 2D  AIThe SynGAP1 missense variant F932V 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 and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.675549 | Disordered | 0.989197 | Binding | 0.293 | 0.858 | 0.500 | -5.728 | Likely Benign | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.392 | Likely Benign | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.32 | Pathogenic | 0.01 | Affected | 0.2137 | 0.3082 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.1072T>A | F358I 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant F358I 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports an uncertain impact. Overall, the preponderance of evidence points to a pathogenic effect for F358I, 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 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -10.636 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.2 | 1.66 | Ambiguous | 1.30 | Ambiguous | 0.95 | Ambiguous | 0.393 | Likely Benign | -4.45 | Deleterious | 0.993 | Probably Damaging | 0.977 | Probably Damaging | 4.07 | Benign | 0.13 | Tolerated | 0.2331 | 0.2821 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.2798A>G | H933R 2D  AIThe SynGAP1 missense variant H933R 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, ESM1b, and AlphaMissense‑Optimized, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of tools (five pathogenic vs. four benign) predict a pathogenic impact. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.987531 | Binding | 0.305 | 0.862 | 0.625 | -4.410 | Likely Benign | 0.650 | Likely Pathogenic | Likely Benign | 0.393 | Likely Benign | -3.84 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.43 | Pathogenic | 0.06 | Tolerated | 0.2074 | 0.2922 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3347G>T | G1116V 2D AIThe SynGAP1 missense variant G1116V is reported in gnomAD (variant ID 6‑33443899‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, creating a single discordant signal. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | 6-33443899-G-T | -6.426 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.393 | Likely Benign | -0.79 | Neutral | 0.626 | Possibly Damaging | 0.375 | Benign | 4.06 | Benign | 0.06 | Tolerated | 4.32 | 2 | 0.1268 | 0.3494 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3764A>T | K1255M 2D  AIThe SynGAP1 missense variant K1255M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign change, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus confirms a likely pathogenic status. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect, 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 | Coiled-coil | 0.637480 | Disordered | 0.417615 | Uncertain | 0.880 | 0.563 | 0.625 | -10.554 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.393 | Likely Benign | -4.82 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.82 | Pathogenic | 0.00 | Affected | 0.0776 | 0.3154 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||||||||||
| c.805A>G | I269V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I269V missense variant has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, 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 lean toward a benign interpretation, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s clinical significance uncertain. This assessment does not contradict any existing ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -8.748 | Likely Pathogenic | 0.344 | Ambiguous | Likely Benign | 0.95 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.72 | Ambiguous | 0.71 | Ambiguous | 0.393 | Likely Benign | -0.72 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 1.87 | Pathogenic | 0.10 | Tolerated | 0.0844 | 0.2859 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
| c.1907T>A | F636Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant F636Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a pathogenic outcome (3/4 votes). High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as inconclusive. Stability‑based tools FoldX, Rosetta, and premPS are uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -9.638 | Likely Pathogenic | 0.695 | Likely Pathogenic | Likely Benign | 0.84 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.68 | Ambiguous | 0.90 | Ambiguous | 0.394 | Likely Benign | -2.89 | Deleterious | 0.927 | Possibly Damaging | 0.836 | Possibly Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1297 | 0.1866 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.3379G>T | G1127W 2D  AIThe SynGAP1 missense variant G1127W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443931‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta’s protein‑folding stability result is unavailable. Overall, the balance of evidence, particularly from the high‑accuracy tools, indicates that the variant is most likely benign. 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. | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | 6-33443931-G-T | 3 | 2.01e-6 | -9.850 | Likely Pathogenic | 0.418 | Ambiguous | Likely Benign | 0.394 | Likely Benign | -1.36 | Neutral | 0.983 | Probably Damaging | 0.665 | Possibly Damaging | 4.79 | Benign | 0.03 | Affected | 4.32 | 4 | 0.0782 | 0.4032 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||
| c.3470G>C | W1157S 2D  AIThe SynGAP1 missense variant W1157S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that W1157S is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -1.158 | Likely Benign | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.394 | Likely Benign | -9.96 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.06 | Pathogenic | 0.00 | Affected | 0.4772 | 0.1227 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.4003G>C | G1335R 2D AIThe SynGAP1 missense variant G1335R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta results are not available. Overall, the preponderance of evidence supports a pathogenic classification for G1335R, 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 | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.921 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.394 | Likely Benign | -5.06 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1071 | 0.5024 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.4004G>T | G1335V 2D AIThe SynGAP1 missense variant G1335V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, 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 pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not conflict with the ClinVar status, which currently has no entry for G1335V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.982 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.394 | Likely Benign | -5.65 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1124 | 0.4195 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.1562A>C | E521A 2D 3DClick to see structure in 3D Viewer AISynGAP1 E521A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls (REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM) and pathogenic calls (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). AlphaMissense‑Optimized is uncertain. High‑accuracy assessments give conflicting results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. No prediction or stability result is missing. Overall, the evidence is evenly split, with six benign and six pathogenic calls, and the two high‑accuracy tools disagree. Therefore, the variant’s impact remains uncertain; it is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -8.997 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.18 | Likely Benign | 0.1 | 0.40 | Likely Benign | 0.29 | Likely Benign | 0.11 | Likely Benign | 0.395 | Likely Benign | -4.12 | Deleterious | 0.998 | Probably Damaging | 0.999 | Probably Damaging | 3.28 | Benign | 0.13 | Tolerated | 0.4041 | 0.5918 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1949A>G | N650S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650S 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 REVEL and FATHMM. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain or inconclusive results come from AlphaMissense‑Optimized, FoldX, Rosetta, Foldetta, and premPS. For high‑accuracy methods, AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta is uncertain. Overall, the majority of available predictions support a pathogenic effect. The variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -11.291 | Likely Pathogenic | 0.916 | Likely Pathogenic | Ambiguous | 0.79 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.11 | Ambiguous | 0.77 | Ambiguous | 0.395 | Likely Benign | -4.98 | Deleterious | 0.996 | Probably Damaging | 0.606 | Possibly Damaging | 3.06 | Benign | 0.02 | Affected | 0.3791 | 0.5090 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.2848G>T | G950C 2D  AIThe SynGAP1 missense variant G950C 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs. 2 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑confidence predictors (five pathogenic vs. four benign) indicate a pathogenic impact. 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. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -9.589 | Likely Pathogenic | 0.092 | Likely Benign | Likely Benign | 0.395 | Likely Benign | -0.35 | Neutral | 0.983 | Probably Damaging | 0.750 | Possibly Damaging | 2.26 | Pathogenic | 0.01 | Affected | 0.1406 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3688A>G | T1230A 2D  AIThe SynGAP1 T1230A missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that classify the variant as benign include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and the Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the consensus and high‑accuracy tools—indicates that the variant is most likely benign, and this conclusion 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 | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -5.236 | Likely Benign | 0.644 | Likely Pathogenic | Likely Benign | 0.395 | Likely Benign | -2.10 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.58 | Benign | 0.03 | Affected | 0.2945 | 0.3231 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.1358A>G | H453R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H453R is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, Rosetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an inconclusive result because FoldX is uncertain and Rosetta is benign. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -9.239 | Likely Pathogenic | 0.573 | Likely Pathogenic | Likely Benign | -0.52 | Ambiguous | 0.1 | 0.37 | Likely Benign | -0.08 | Likely Benign | 0.56 | Ambiguous | 0.396 | Likely Benign | -7.91 | Deleterious | 0.993 | Probably Damaging | 0.957 | Probably Damaging | 3.53 | Benign | 0.39 | Tolerated | 0.1646 | 0.2031 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.1952A>C | E651A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E651A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicting it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign impact. Overall, the balance of evidence leans toward a benign classification, and this conclusion does not contradict the absence of a ClinVar record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -8.694 | Likely Pathogenic | 0.610 | Likely Pathogenic | Likely Benign | 0.38 | Likely Benign | 0.1 | 0.52 | Ambiguous | 0.45 | Likely Benign | 0.23 | Likely Benign | 0.396 | Likely Benign | -4.54 | Deleterious | 0.986 | Probably Damaging | 0.875 | Possibly Damaging | 3.33 | Benign | 0.13 | Tolerated | 0.3926 | 0.5551 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2174T>C | L725P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools—FoldX, Rosetta, Foldetta, 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)—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) 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 collective predictions, 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 | 0.557691 | Disordered | 0.455613 | Uncertain | 0.911 | 0.491 | 0.625 | -15.390 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 4.91 | Destabilizing | 0.1 | 9.02 | Destabilizing | 6.97 | Destabilizing | 1.82 | Destabilizing | 0.396 | Likely Benign | -6.08 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.3796 | 0.1664 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.2833C>G | H945D 2D  AIThe SynGAP1 missense variant H945D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for H945D, 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 | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | -6.572 | Likely Benign | 0.191 | Likely Benign | Likely Benign | 0.396 | Likely Benign | -0.18 | Neutral | 0.982 | Probably Damaging | 0.870 | Possibly Damaging | 5.02 | Benign | 0.04 | Affected | 0.2803 | 0.2275 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3382G>A | G1128R 2D AIThe SynGAP1 missense variant G1128R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.009 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.396 | Likely Benign | -0.79 | Neutral | 0.846 | Possibly Damaging | 0.346 | Benign | 4.38 | Benign | 0.12 | Tolerated | 0.0950 | 0.4725 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3895C>A | L1299I 2D  AIThe SynGAP1 missense variant L1299I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -5.264 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.396 | Likely Benign | 0.71 | Neutral | 0.003 | Benign | 0.004 | Benign | 3.20 | Benign | 1.00 | Tolerated | 0.1014 | 0.3893 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.500A>T | D167V 2D AIThe SynGAP1 D167V variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -14.388 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.396 | Likely Benign | -4.03 | Deleterious | 0.535 | Possibly Damaging | 0.247 | Benign | 3.92 | Benign | 0.00 | Affected | 0.0709 | 0.6905 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.994G>A | D332N 2D  3DClick to see structure in 3D Viewer AISynGAP1 D332N is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, Rosetta, premPS, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; SGM‑Consensus indicates a likely pathogenic outcome. FoldX and Foldetta give uncertain results. High‑accuracy tools show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, but the high‑accuracy AlphaMissense‑Optimized result is benign and Foldetta is inconclusive. Thus, the variant is most likely pathogenic based on the collective evidence, 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 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -10.931 | Likely Pathogenic | 0.771 | Likely Pathogenic | Likely Benign | 1.20 | Ambiguous | 0.1 | -0.16 | Likely Benign | 0.52 | Ambiguous | 0.49 | Likely Benign | 0.396 | Likely Benign | -4.14 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.0785 | 0.3963 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| 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.3382G>C | G1128R 2D AIThe SynGAP1 missense variant G1128R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.009 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.397 | Likely Benign | -0.79 | Neutral | 0.846 | Possibly Damaging | 0.346 | Benign | 4.38 | Benign | 0.12 | Tolerated | 0.0950 | 0.4725 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3389A>C | K1130T 2D AIThe SynGAP1 missense variant K1130T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) which classifies it as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is Uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack 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 Benign | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -3.550 | Likely Benign | 0.829 | Likely Pathogenic | Ambiguous | 0.397 | Likely Benign | -1.38 | Neutral | 0.481 | Possibly Damaging | 0.157 | Benign | 5.47 | Benign | 0.00 | Affected | 0.2572 | 0.4349 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||||||||||||
| c.3504C>G | I1168M 2D  AIThe SynGAP1 missense variant I1168M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, 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, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for I1168M, 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 | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -3.471 | Likely Benign | 0.568 | Likely Pathogenic | Likely Benign | 0.397 | Likely Benign | -0.79 | Neutral | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 5.45 | Benign | 0.04 | Affected | 0.0744 | 0.3335 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||||||||
| c.3521A>G | E1174G 2D AIThe SynGAP1 E1174G missense change 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, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for E1174G, 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 | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -4.197 | Likely Benign | 0.714 | Likely Pathogenic | Likely Benign | 0.397 | Likely Benign | -2.20 | Neutral | 0.818 | Possibly Damaging | 0.353 | Benign | 5.42 | Benign | 0.01 | Affected | 0.2665 | 0.5614 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.1256A>C | E419A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -10.951 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 0.56 | Ambiguous | 0.1 | 0.94 | Ambiguous | 0.75 | Ambiguous | 0.28 | Likely Benign | 0.398 | Likely Benign | -5.60 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0.4051 | 0.6705 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| 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.1457A>C | E486A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, premPS, SIFT, and FATHMM, whereas pathogenic predictions are made by SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore unavailable. Overall, the majority of evidence supports a pathogenic effect. The prediction aligns with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -11.902 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.0 | 0.32 | Likely Benign | 0.48 | Likely Benign | -0.03 | Likely Benign | 0.398 | Likely Benign | -5.17 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.44 | Benign | 0.39 | Tolerated | 0.3561 | 0.5859 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1627C>G | L543V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—classify the variant as pathogenic. AlphaMissense‑Optimized is inconclusive (uncertain). High‑accuracy assessments further support pathogenicity: the SGM‑Consensus predicts “Likely Pathogenic,” and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. AlphaMissense‑Optimized remains uncertain. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -11.561 | Likely Pathogenic | 0.908 | Likely Pathogenic | Ambiguous | 3.09 | Destabilizing | 0.3 | 2.03 | Destabilizing | 2.56 | Destabilizing | 1.28 | Destabilizing | 0.398 | Likely Benign | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.99 | Pathogenic | 0.01 | Affected | 0.1334 | 0.2028 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1783C>G | L595V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L595V 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 premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked uncertain include FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy consensus methods give a clearer picture: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the majority of evidence points toward 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 | GAP | 0.015344 | Structured | 0.128444 | Uncertain | 0.920 | 0.150 | 0.000 | -13.490 | Likely Pathogenic | 0.905 | Likely Pathogenic | Ambiguous | 1.29 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.77 | Ambiguous | 1.01 | Destabilizing | 0.398 | Likely Benign | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.78 | Benign | 0.01 | Affected | 0.1441 | 0.3406 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1867C>A | L623I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign calls come only from REVEL and PROVEAN, while pathogenic calls are made by FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which is derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Overall, the preponderance of evidence 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 | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -11.952 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 3.15 | Destabilizing | 0.5 | 1.90 | Ambiguous | 2.53 | Destabilizing | 1.13 | Destabilizing | 0.398 | Likely Benign | -1.99 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.63 | Pathogenic | 0.02 | Affected | 0.1109 | 0.3767 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.3593A>C | Y1198S 2D  AIThe SynGAP1 missense variant Y1198S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a 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 | Coiled-coil | 0.626927 | Disordered | 0.439379 | Uncertain | 0.853 | 0.593 | 0.250 | -13.252 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.398 | Likely Benign | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.45 | Pathogenic | 0.38 | Tolerated | 0.4901 | 0.1043 | -3 | -2 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||||||||||
| c.3665G>T | R1222M 2D  AIThe SynGAP1 missense variant R1222M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is “Likely Pathogenic,” and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; 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 | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -12.190 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.398 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.46 | Pathogenic | 0.20 | Tolerated | 0.1069 | 0.2559 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||
| c.1255G>A | E419K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E419K missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Foldetta and Rosetta give uncertain results and are not counted in either group. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus predicts likely pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact for E419K. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -12.257 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.01 | Likely Benign | 0.1 | 1.30 | Ambiguous | 0.66 | Ambiguous | -0.03 | Likely Benign | 0.399 | Likely Benign | -3.75 | Deleterious | 0.998 | Probably Damaging | 0.975 | Probably Damaging | 3.36 | Benign | 0.07 | Tolerated | 0.2759 | 0.6899 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| 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.1450T>A | F484I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484I 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. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are inconclusive or missing. Based on the preponderance of evidence, 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 | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -16.197 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.62 | Destabilizing | 0.2 | 5.62 | Destabilizing | 5.62 | Destabilizing | 1.33 | Destabilizing | 0.399 | Likely Benign | -5.70 | Deleterious | 0.894 | Possibly Damaging | 0.332 | Benign | 2.74 | Benign | 0.00 | Affected | 0.1516 | 0.1885 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1708G>T | A570S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A570S 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 outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, and ESM1b) yield 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, and PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the majority of reliable predictions indicate 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 | 0.046336 | Structured | 0.054494 | Uncertain | 0.932 | 0.263 | 0.000 | -7.893 | In-Between | 0.194 | Likely Benign | Likely Benign | 0.77 | Ambiguous | 0.1 | 1.68 | Ambiguous | 1.23 | Ambiguous | 0.51 | Ambiguous | 0.399 | Likely Benign | -2.26 | Neutral | 0.983 | Probably Damaging | 0.993 | Probably Damaging | -1.19 | Pathogenic | 0.17 | Tolerated | 0.2091 | 0.3256 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.2002T>G | S668A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 S668A 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, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools—AlphaMissense‑Default and FoldX—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Taking all evidence together, the majority of predictions (seven benign versus four pathogenic) and the two high‑accuracy benign calls suggest that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -12.011 | Likely Pathogenic | 0.506 | Ambiguous | Likely Benign | 0.73 | Ambiguous | 0.3 | -0.44 | Likely Benign | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.399 | Likely Benign | -2.99 | Deleterious | 0.887 | Possibly Damaging | 0.738 | Possibly Damaging | 3.28 | Benign | 0.19 | Tolerated | 0.4866 | 0.3967 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||
| 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.2534A>G | D845G 2D  AIThe SynGAP1 missense variant D845G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL classifies it as benign, whereas the remaining 11 predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a Likely Pathogenic status; Foldetta results are not available. Taken together, the preponderance of evidence indicates that D845G is most likely pathogenic, and this assessment does not conflict with the current ClinVar record, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.553315 | Disordered | 0.599971 | Binding | 0.297 | 0.827 | 0.500 | -8.209 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.399 | Likely Benign | -4.96 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 2.06 | Pathogenic | 0.00 | Affected | 0.3953 | 0.6740 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.2834A>T | H945L 2D AIThe SynGAP1 missense variant H945L is reported in gnomAD (ID 6‑33443386‑A‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | 6-33443386-A-T | 2 | 1.24e-6 | -4.741 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.399 | Likely Benign | 0.16 | Neutral | 0.948 | Possibly Damaging | 0.863 | Possibly Damaging | 5.05 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.2085 | 0.4526 | -3 | -2 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||
| c.3164G>T | G1055V 2D AIThe SynGAP1 missense variant G1055V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while ESM1b remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -7.434 | In-Between | 0.114 | Likely Benign | Likely Benign | 0.399 | Likely Benign | 0.26 | Neutral | 0.818 | Possibly Damaging | 0.222 | Benign | 3.28 | Benign | 0.17 | Tolerated | 0.1399 | 0.3694 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3383G>T | G1128V 2D AIThe SynGAP1 missense variant G1128V is reported in gnomAD (variant ID 6‑33443935‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | 6-33443935-G-T | -5.111 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.399 | Likely Benign | -0.69 | Neutral | 0.611 | Possibly Damaging | 0.185 | Benign | 4.39 | Benign | 0.09 | Tolerated | 4.32 | 4 | 0.1358 | 0.3922 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.3776T>C | I1259T 2D  AIThe SynGAP1 missense variant I1259T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic, two benign) and Foldetta results are unavailable. Overall, the majority of evidence (six pathogenic vs. three benign predictions) points to a pathogenic impact. The variant is most likely pathogenic based on current predictions, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -10.057 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.399 | Likely Benign | -2.47 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.0991 | 0.1051 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.989A>C | D330A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D330A 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 SIFT, while a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized—do not provide definitive evidence. High‑accuracy methods give the following: SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; AlphaMissense‑Optimized is uncertain; Foldetta is also uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for D330A. This conclusion is not contradicted by ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -14.051 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 1.75 | Ambiguous | 0.3 | 1.06 | Ambiguous | 1.41 | Ambiguous | 0.60 | Ambiguous | 0.399 | Likely Benign | -5.49 | Deleterious | 0.961 | Probably Damaging | 0.655 | Possibly Damaging | 0.93 | Pathogenic | 0.11 | Tolerated | 0.4087 | 0.4476 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1556A>T | E519V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E519V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight the discord: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates benign stability. Overall, the preponderance of evidence points to a pathogenic effect for E519V. This conclusion does not conflict with ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.513 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.59 | Ambiguous | 0.0 | -0.40 | Likely Benign | 0.10 | Likely Benign | 0.16 | Likely Benign | 0.400 | Likely Benign | -6.33 | Deleterious | 0.996 | Probably Damaging | 0.991 | Probably Damaging | 3.20 | Benign | 0.00 | Affected | 0.0825 | 0.4369 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2770C>A | P924T 2D  AIThe SynGAP1 missense variant P924T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that P924T is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.521092 | Disordered | 0.971858 | Binding | 0.293 | 0.846 | 0.250 | -6.360 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.400 | Likely Benign | -6.03 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.67 | Pathogenic | 0.00 | Affected | 0.1190 | 0.4009 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3526G>A | E1176K 2D AIThe SynGAP1 E1176K missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves as Likely Benign. High‑accuracy assessments further show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta) is not available for this residue. Because the majority of evidence, including the consensus score, points to a benign effect and no ClinVar entry contradicts this, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.538167 | Disordered | 0.572075 | Binding | 0.525 | 0.715 | 0.250 | -4.240 | Likely Benign | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.400 | Likely Benign | -1.41 | Neutral | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 5.54 | Benign | 0.18 | Tolerated | 0.1658 | 0.6321 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3577G>C | D1193H 2D  AIThe SynGAP1 missense variant D1193H is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized inconclusive, an SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) that is benign, and no Foldetta result available. Overall, the majority of conventional tools predict pathogenicity, while the SGM Consensus suggests benign. Based on the combined evidence, 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. | Coiled-coil | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | -7.633 | In-Between | 0.900 | Likely Pathogenic | Ambiguous | 0.400 | Likely Benign | -2.31 | Neutral | 0.977 | Probably Damaging | 0.924 | Probably Damaging | 5.41 | Benign | 0.00 | Affected | 0.1239 | 0.4584 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3779A>T | K1260M 2D AIThe SynGAP1 missense variant K1260M 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 algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—classify the substitution as pathogenic. High‑accuracy assessments further support a deleterious impact: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Pathogenic”; AlphaMissense‑Optimized yields an uncertain result, and Foldetta’s stability prediction is unavailable. Taken together, the evidence overwhelmingly points to a pathogenic effect for K1260M. This conclusion is consistent with the lack 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 | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -10.938 | Likely Pathogenic | 0.887 | Likely Pathogenic | Ambiguous | 0.400 | Likely Benign | -4.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.0746 | 0.3366 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||||||||||
| c.1996G>A | E666K 2D AIThe SynGAP1 missense variant E666K 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 agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely 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 currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -11.367 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.20 | Likely Benign | 0.6 | 0.30 | Likely Benign | 0.25 | Likely Benign | 0.43 | Likely Benign | 0.401 | Likely Benign | -3.26 | Deleterious | 0.992 | Probably Damaging | 0.717 | Possibly Damaging | 3.46 | Benign | 0.05 | Affected | 0.2953 | 0.5300 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| 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.2089T>A | W697R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W697R 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 predict a pathogenic effect: SGM‑Consensus, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, and premPS. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence from multiple pathogenic‑predicting tools indicates that W697R 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 | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | -10.020 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.14 | Ambiguous | 0.1 | 1.18 | Ambiguous | 1.16 | Ambiguous | 1.25 | Destabilizing | 0.401 | Likely Benign | -9.50 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 3.46 | 13 | 0.3944 | 0.0612 | 2 | -3 | -3.6 | -30.03 | 254.4 | -41.2 | 0.0 | 0.0 | -0.7 | 0.0 | X | Potentially Benign | The indole ring of Trp697, located on the outer surface of an α-helix (res. Leu685-Val699), is not involved in any long-lasting interactions in the WT simulations. In the variant simulations, the positively charged guanidinium side chain of Arg697 occasionally forms hydrogen bonds with nearby residues, such as Ser722 and Asn719. However, similar to Trp697 in the WT, Arg697 does not form any long-lasting interactions and thus does not induce any negative structural effects in the simulations. | ||||||||||||||||||
| c.2089T>C | W697R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W697R is listed in ClinVar as Benign (ClinVar ID 703213.0) and is present in the gnomAD database (gnomAD ID 6‑33441348‑T‑C). Functional prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence from multiple pathogenic‑predicting tools suggests that the variant is most likely pathogenic, which contradicts its current ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | Likely Benign | 1 | 6-33441348-T-C | 1 | 6.20e-7 | -10.020 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.14 | Ambiguous | 0.1 | 1.18 | Ambiguous | 1.16 | Ambiguous | 1.25 | Destabilizing | 0.401 | Likely Benign | -9.50 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 3.46 | 13 | 0.3944 | 0.0612 | 2 | -3 | -3.6 | -30.03 | 254.4 | -41.2 | 0.0 | 0.0 | -0.7 | 0.0 | X | Potentially Benign | The indole ring of Trp697, located on the outer surface of an α-helix (res. Leu685-Val699), is not involved in any long-lasting interactions in the WT simulations. In the variant simulations, the positively charged guanidinium side chain of Arg697 occasionally forms hydrogen bonds with nearby residues, such as Ser722 and Asn719. However, similar to Trp697 in the WT, Arg697 does not form any long-lasting interactions and thus does not induce any negative structural effects in the simulations. | |||||||||||||
| c.3184G>T | G1062W 2D AIThe SynGAP1 missense variant G1062W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which labels the variant as “Likely Benign.” Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b, all of which classify the change as damaging. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -9.667 | Likely Pathogenic | 0.315 | Likely Benign | Likely Benign | 0.401 | Likely Benign | -1.38 | Neutral | 0.993 | Probably Damaging | 0.890 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 0.0908 | 0.4246 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3395C>A | S1132Y 2D AIThe SynGAP1 missense variant S1132Y is listed in ClinVar as a benign alteration (ClinVar ID 845357.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | Likely Benign | 1 | -5.894 | Likely Benign | 0.392 | Ambiguous | Likely Benign | 0.401 | Likely Benign | -1.76 | Neutral | 0.500 | Possibly Damaging | 0.208 | Benign | 5.40 | Benign | 0.09 | Tolerated | 4.32 | 4 | 0.0889 | 0.5233 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||
| c.1169G>C | G390A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and Rosetta. The high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as pathogenic. FoldX alone is inconclusive. Overall, the majority of evidence points to a benign impact, 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 Benign | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -6.768 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 1.96 | Ambiguous | 0.4 | 2.03 | Destabilizing | 2.00 | Destabilizing | 0.02 | Likely Benign | 0.402 | Likely Benign | -0.55 | Neutral | 0.143 | Benign | 0.028 | Benign | 1.33 | Pathogenic | 0.05 | Affected | 0.4130 | 0.5053 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1258T>G | F420V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts Pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy tool consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -11.849 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.1 | 3.35 | Destabilizing | 3.39 | Destabilizing | 1.58 | Destabilizing | 0.402 | Likely Benign | -6.41 | Deleterious | 0.495 | Possibly Damaging | 0.191 | Benign | 3.16 | Benign | 0.01 | Affected | 0.2038 | 0.2022 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.2141T>G | L714R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.763 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.38 | Destabilizing | 0.2 | 7.54 | Destabilizing | 5.96 | Destabilizing | 2.09 | Destabilizing | 0.402 | Likely Benign | -5.62 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.1186 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2183C>A | P728H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728H 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 REVEL, which scores the variant as benign. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, all of which predict a deleterious impact. Predictions that are inconclusive or uncertain are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect for P728H, and this conclusion 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 | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -8.897 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.94 | Ambiguous | 0.0 | 0.86 | Ambiguous | 0.90 | Ambiguous | 0.64 | Ambiguous | 0.402 | Likely Benign | -7.23 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.65 | Pathogenic | 0.00 | Affected | 0.1993 | 0.3016 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||
| c.2183C>T | P728L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, and premPS, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact; FoldX and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for P728L. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -11.125 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.79 | Ambiguous | 0.0 | 0.15 | Likely Benign | 0.47 | Likely Benign | 0.20 | Likely Benign | 0.402 | Likely Benign | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.2321 | 0.4713 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.2411A>T | D804V 2D AIThe SynGAP1 missense variant D804V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict a pathogenic impact. The AlphaMissense‑Optimized score is uncertain, providing no definitive evidence. High‑accuracy assessments show that the SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; AlphaMissense‑Optimized remains inconclusive, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for D804V, and 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. | Likely Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -8.143 | Likely Pathogenic | 0.832 | Likely Pathogenic | Ambiguous | 0.402 | Likely Benign | -4.77 | Deleterious | 0.997 | Probably Damaging | 0.951 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 0.1196 | 0.6981 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||
| c.2849G>A | G950D 2D AIThe SynGAP1 missense variant G950D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -7.515 | In-Between | 0.245 | Likely Benign | Likely Benign | 0.402 | Likely Benign | -0.61 | Neutral | 0.411 | Benign | 0.131 | Benign | 2.26 | Pathogenic | 0.02 | Affected | 0.1874 | 0.2826 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3373G>T | G1125W 2D AIThe SynGAP1 missense variant G1125W 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the balance of evidence, especially from the high‑accuracy tools, points to a benign classification. This conclusion is not contradicted by any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | -11.684 | Likely Pathogenic | 0.372 | Ambiguous | Likely Benign | 0.402 | Likely Benign | -1.10 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 4.50 | Benign | 0.00 | Affected | 0.0924 | 0.4046 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.3581G>C | R1194T 2D  AIThe SynGAP1 missense variant R1194T 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, PROVEAN, ESM1b, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are split, with four tools supporting benign and four supporting pathogenic, and the high‑accuracy consensus is conflicting. Based on the available 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 | Coiled-coil | 0.685117 | Disordered | 0.425297 | Uncertain | 0.796 | 0.602 | 0.375 | -4.875 | Likely Benign | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.402 | Likely Benign | -1.96 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.50 | Benign | 0.02 | Affected | 0.1866 | 0.3706 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||
| c.3602A>T | E1201V 2D AIThe SynGAP1 missense variant E1201V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign change, whereas all other evaluated algorithms—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 this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status. No Foldetta stability analysis is available for this variant. Overall, the preponderance of evidence from multiple prediction tools and consensus methods indicates that E1201V 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 | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -10.865 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.402 | Likely Benign | -5.43 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.59 | Pathogenic | 0.00 | Affected | 0.0455 | 0.6308 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.1884G>C | K628N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K628N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—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)—classify the variant as pathogenic or likely pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability predictions and are therefore treated as unavailable evidence. High‑accuracy assessments specifically show AlphaMissense‑Optimized predicting pathogenicity, the SGM‑Consensus indicating a likely pathogenic status, and Foldetta yielding an uncertain result. Based on the overwhelming agreement among the majority of prediction tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | -12.284 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.78 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.69 | Ambiguous | 1.11 | Destabilizing | 0.403 | Likely Benign | -4.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.37 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.2740 | 0.1254 | 0 | 1 | 0.4 | -14.07 | |||||||||||||||||||||||||||
| c.1884G>T | K628N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K628N is catalogued in gnomAD (6‑33440936‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: a single benign prediction from REVEL, and a consensus of nine pathogenic predictions from premPS, 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, also labels the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and therefore does not alter the overall interpretation. Consequently, the variant is most likely pathogenic according to the available computational evidence, 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 | 0.088832 | Structured | 0.035486 | Uncertain | 0.957 | 0.229 | 0.000 | 6-33440936-G-T | 1 | 6.20e-7 | -12.284 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.78 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.69 | Ambiguous | 1.11 | Destabilizing | 0.403 | Likely Benign | -4.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.37 | Pathogenic | 0.00 | Affected | 3.37 | 34 | 0.2740 | 0.1254 | 0 | 1 | 0.4 | -14.07 | ||||||||||||||||||||||||
| c.3122C>T | P1041L 2D AIThe SynGAP1 missense variant P1041L 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, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and polyPhen‑2 HumDiv. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -4.901 | Likely Benign | 0.399 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -3.14 | Deleterious | 0.905 | Possibly Damaging | 0.375 | Benign | 5.46 | Benign | 1.00 | Tolerated | 0.2357 | 0.6664 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.3184G>A | G1062R 2D AIThe SynGAP1 missense variant G1062R is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443736‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, polyPhen‑2 HumVar, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta results are unavailable. 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 | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | Conflicting | 2 | 6-33443736-G-A | 7 | 4.35e-6 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1013 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.3434A>C | N1145T 2D  AIThe SynGAP1 missense variant N1145T is reported in gnomAD (ID 6‑33444469‑A‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict the variant to be pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact for N1145T, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | 6-33444469-A-C | 1 | 6.20e-7 | -1.915 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 0.403 | Likely Benign | -2.17 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.45 | Benign | 0.07 | Tolerated | 4.32 | 4 | 0.1418 | 0.7209 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||||||
| c.3515A>C | H1172P 2D  AIThe SynGAP1 missense variant H1172P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, 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. | Likely Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -2.871 | Likely Benign | 0.653 | Likely Pathogenic | Likely Benign | 0.403 | Likely Benign | -2.09 | Neutral | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 5.42 | Benign | 0.02 | Affected | 0.2033 | 0.4128 | 0 | -2 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||||||||
| c.3607C>G | H1203D 2D AIThe SynGAP1 missense variant H1203D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | Uncertain | 2 | -6.729 | Likely Benign | 0.525 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -1.89 | Neutral | 0.473 | Possibly Damaging | 0.265 | Benign | 5.51 | Benign | 0.24 | Tolerated | 3.77 | 5 | 0.1926 | 0.0530 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||
| c.3806T>A | V1269E 2D  AIThe SynGAP1 missense change V1269E is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that flag the variant as benign include only REVEL, whereas the remaining predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Pathogenic” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | Uncertain | 1 | -11.418 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.403 | Likely Benign | -5.05 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.09 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0899 | 0.1557 | -2 | -2 | -7.7 | 29.98 | ||||||||||||||||||||||||||||||||||
| c.626T>A | V209E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining 13 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 methods further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, V209E 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 | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -14.366 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 1.3 | 2.35 | Destabilizing | 2.94 | Destabilizing | 1.52 | Destabilizing | 0.403 | Likely Benign | -4.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.65 | Benign | 0.00 | Affected | 0.0826 | 0.1652 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.1025A>G | Y342C 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y342C is listed in ClinVar as Benign (ClinVar ID 1213078.0) and is observed in gnomAD (ID 6‑33437930‑A‑G). Across general prediction tools, benign calls are made by REVEL and AlphaMissense‑Optimized, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by premPS and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicting Benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting Pathogenic. Overall, the majority of predictions support a pathogenic effect, contradicting the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | Benign/Likely benign | 2 | 6-33437930-A-G | 21 | 1.30e-5 | -7.596 | In-Between | 0.682 | Likely Pathogenic | Likely Benign | 2.48 | Destabilizing | 0.1 | 2.73 | Destabilizing | 2.61 | Destabilizing | 0.92 | Ambiguous | 0.404 | Likely Benign | -6.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.72 | Pathogenic | 0.02 | Affected | 3.37 | 25 | 0.2836 | 0.2870 | 0 | -2 | 3.8 | -60.04 | 242.4 | 62.8 | 0.1 | 0.0 | -0.1 | 0.2 | Potentially Pathogenic | The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. This phenol ring contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Cys342 side chain cannot participate in the stack formation. Instead, its thiol group forms a hydrogen bond with the backbone carbonyl group of Leu327. Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association; however, this phenomenon cannot be addressed using solvent-only simulations. Notably, the thiol group of cysteine is not a particularly strong hydrogen-bonding partner, which could mitigate the negative effects of the residue swap. | ||||||||||||||
| c.1771G>C | A591P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A591P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely converge on a pathogenic effect: pathogenic predictions come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). Benign predictions are limited to REVEL 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) also indicates pathogenic. Consequently, the variant is most likely pathogenic, a conclusion that contrasts with its ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | Uncertain | 1 | -14.479 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 3.78 | Destabilizing | 0.3 | 7.29 | Destabilizing | 5.54 | Destabilizing | 1.45 | Destabilizing | 0.404 | Likely Benign | -4.41 | Deleterious | 0.995 | Probably Damaging | 0.853 | Possibly Damaging | 3.35 | Benign | 0.01 | Affected | 3.37 | 35 | 0.1872 | 0.3087 | 1 | -1 | -3.4 | 26.04 | 191.5 | -10.1 | 0.2 | 0.1 | 0.4 | 0.1 | X | Potentially Pathogenic | The methyl group of the Ala591 side chain, located in the middle of an α helix (res. Glu582-Met603), packs against hydrophobic residues (e.g., Ile483, Phe484) of an opposing partially helical loop (res. Phe476-Asn487).In the variant simulations, Pro591 lacks a free backbone amide group and, therefore, cannot form a hydrogen bond with the backbone carbonyl of Arg587 as Ala591 does in the WT. This notably weakens the α helix integrity and compromises the continuity of the helix. In reality, the effect on the structure during protein folding could be more severe. | ||||||||||||||||
| c.1913A>C | K638T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K638T is not reported in ClinVar and is absent from gnomAD. Consensus from standard in silico predictors shows a split: benign calls come from REVEL, Rosetta, premPS, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; FoldX and Foldetta are inconclusive. High‑accuracy assessments give AlphaMissense‑Optimized a benign score, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic effect for K638T. This prediction 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 | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -8.856 | Likely Pathogenic | 0.775 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.23 | Likely Benign | 0.55 | Ambiguous | 0.07 | Likely Benign | 0.404 | Likely Benign | -5.39 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.52 | Benign | 0.03 | Affected | 0.1632 | 0.2619 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| 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.3647T>A | L1216Q 2D AIThe SynGAP1 missense variant L1216Q 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 REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as pathogenic; Foldetta results are not available. Based on the collective evidence, 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 | Coiled-coil | 0.580690 | Disordered | 0.504713 | Binding | 0.863 | 0.563 | 0.250 | -8.731 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.404 | Likely Benign | -4.12 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.23 | Pathogenic | 0.00 | Affected | 0.0939 | 0.0488 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.4004G>A | G1335D 2D AIThe SynGAP1 missense variant G1335D is reported in ClinVar as “not listed” and is present in gnomAD (variant ID 6‑33451878‑G‑A). Functional prediction tools that agree on a benign effect are REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, 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 impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and the SGM‑Consensus suggests that G1335D 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 | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | 6-33451878-G-A | -5.687 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.404 | Likely Benign | -4.42 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2120 | 0.3702 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||
| c.778G>A | V260I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V260I missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts benign. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.254060 | Structured | 0.382651 | Uncertain | 0.888 | 0.259 | 0.250 | -7.525 | In-Between | 0.104 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.06 | Likely Benign | -0.14 | Likely Benign | 0.404 | Likely Benign | -0.85 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.83 | Benign | 0.19 | Tolerated | 0.0559 | 0.3704 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.1213C>A | R405S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts Pathogenic. Taken together, the overwhelming majority of evidence indicates that R405S is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.326 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 2.66 | Destabilizing | 0.5 | 2.08 | Destabilizing | 2.37 | Destabilizing | 1.22 | Destabilizing | 0.405 | Likely Benign | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.67 | Benign | 0.05 | Affected | 0.2829 | 0.4646 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.1440G>C | E480D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, whereas polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta remains uncertain. Overall, the balance of evidence favors a benign classification for E480D, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | 0.405 | Likely Benign | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 0.1526 | 0.4130 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1440G>T | E480D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E480D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and ESM1b, while polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic outcome. The remaining tools—FoldX, Rosetta, premPS, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta providing no definitive stability change. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | -3.001 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.2 | 1.39 | Ambiguous | 1.01 | Ambiguous | 0.61 | Ambiguous | 0.405 | Likely Benign | -0.77 | Neutral | 0.989 | Probably Damaging | 0.979 | Probably Damaging | -1.27 | Pathogenic | 0.28 | Tolerated | 0.1526 | 0.4130 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1750A>G | I584V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I584V is catalogued in gnomAD (ID 6‑33440802‑A‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and FATHMM. Two tools (FoldX and ESM1b) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign (2 benign vs. 1 pathogenic vote), and Foldetta predicts benign stability. Overall, the majority of evidence points to a benign impact. 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. | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | 6-33440802-A-G | 1 | 6.20e-7 | -7.562 | In-Between | 0.234 | Likely Benign | Likely Benign | 0.67 | Ambiguous | 0.1 | 0.29 | Likely Benign | 0.48 | Likely Benign | 1.16 | Destabilizing | 0.405 | Likely Benign | -0.95 | Neutral | 0.642 | Possibly Damaging | 0.349 | Benign | -1.18 | Pathogenic | 0.18 | Tolerated | 3.37 | 34 | 0.1007 | 0.2659 | 3 | 4 | -0.3 | -14.03 | |||||||||||||||||||||||||
| c.1878T>G | I626M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I626M 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. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and premPS 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, and PROVEAN) predicts likely pathogenic; Foldetta’s stability prediction is 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 | GAP | 0.109221 | Structured | 0.040732 | Uncertain | 0.970 | 0.223 | 0.000 | -11.407 | Likely Pathogenic | 0.618 | Likely Pathogenic | Likely Benign | 0.72 | Ambiguous | 0.1 | 1.78 | Ambiguous | 1.25 | Ambiguous | 0.92 | Ambiguous | 0.405 | Likely Benign | -2.76 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.06 | Benign | 0.02 | Affected | 0.0661 | 0.1959 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.3346G>T | G1116W 2D AIThe SynGAP1 missense variant G1116W is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443898‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta’s protein‑folding stability result is unavailable. Taken together, the majority of reliable predictors and the consensus high‑accuracy tools indicate a benign effect. 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. | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | 6-33443898-G-T | -9.448 | Likely Pathogenic | 0.356 | Ambiguous | Likely Benign | 0.405 | Likely Benign | -1.27 | Neutral | 0.996 | Probably Damaging | 0.946 | Probably Damaging | 4.04 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0776 | 0.4046 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||
| c.3466G>C | A1156P 2D AIThe SynGAP1 missense variant A1156P 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 REVEL and ESM1b, whereas the remaining tools—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence indicates that A1156P 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 | 0.720929 | Disordered | 0.871395 | Binding | 0.294 | 0.861 | 0.500 | -2.847 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.405 | Likely Benign | -3.49 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.59 | Pathogenic | 0.00 | Affected | 0.1718 | 0.5104 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3518T>C | I1173T 2D AIThe SynGAP1 missense variant I1173T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for I1173T, 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 | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -3.162 | Likely Benign | 0.441 | Ambiguous | Likely Benign | 0.405 | Likely Benign | -1.18 | Neutral | 0.451 | Benign | 0.265 | Benign | 5.46 | Benign | 0.05 | Affected | 0.1016 | 0.0821 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||||
| c.3688A>T | T1230S 2D  AIThe SynGAP1 missense variant T1230S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for T1230S, 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 | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -5.974 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.405 | Likely Benign | -1.47 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 5.64 | Benign | 0.06 | Tolerated | 0.2405 | 0.3321 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.959T>A | V320D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and SIFT; pathogenic predictions from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods FoldX and Rosetta returned uncertain results, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also yielded an uncertain prediction. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the lack of ClinVar annotation and gnomAD absence. Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status because ClinVar has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -11.269 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.99 | Ambiguous | 1.0 | 1.67 | Ambiguous | 1.83 | Ambiguous | 1.50 | Destabilizing | 0.405 | Likely Benign | -5.58 | Deleterious | 0.999 | Probably Damaging | 0.972 | Probably Damaging | 1.93 | Pathogenic | 0.07 | Tolerated | 0.1101 | 0.0482 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1082A>T | Q361L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q361L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. 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 (8 benign vs 5 pathogenic) favor a benign effect, and this consensus does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign based on current predictions, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | -10.678 | Likely Pathogenic | 0.238 | Likely Benign | Likely Benign | 0.12 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.29 | Likely Benign | 0.21 | Likely Benign | 0.406 | Likely Benign | -3.95 | Deleterious | 0.987 | Probably Damaging | 0.953 | Probably Damaging | 1.71 | Pathogenic | 0.06 | Tolerated | 0.0720 | 0.5213 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||
| c.1148G>T | G383V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383V 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, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 HumDiv, and SIFT. 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 pathogenic. Overall, the majority of predictions lean toward a benign impact, 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. | Likely Benign | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -5.769 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 5.13 | Destabilizing | 2.1 | 4.06 | Destabilizing | 4.60 | Destabilizing | -0.26 | Likely Benign | 0.406 | Likely Benign | -0.72 | Neutral | 0.668 | Possibly Damaging | 0.207 | Benign | 4.12 | Benign | 0.01 | Affected | 0.1597 | 0.3493 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1241T>C | M414T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant M414T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta; Rosetta remains uncertain. High‑accuracy methods all support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta predicts a destabilizing, pathogenic outcome. Consequently, the consensus of the most reliable predictors classifies M414T as pathogenic, with no conflict with the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -8.698 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 2.04 | Destabilizing | 0.1 | 1.96 | Ambiguous | 2.00 | Destabilizing | 1.27 | Destabilizing | 0.406 | Likely Benign | -5.00 | Deleterious | 0.997 | Probably Damaging | 0.972 | Probably Damaging | 3.41 | Benign | 0.08 | Tolerated | 0.1771 | 0.1976 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||
| c.3152G>C | G1051A 2D AIThe SynGAP1 missense variant G1051A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates a benign effect, 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 | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -6.406 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.406 | Likely Benign | -0.14 | Neutral | 0.009 | Benign | 0.004 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 0.3353 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1025A>C | Y342S 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant Y342S is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the majority of algorithms predict a pathogenic impact: FoldX, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and the Foldetta stability assessment (combining FoldX‑MD and Rosetta). Uncertain results come from premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods specifically give AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | Uncertain | 2 | -7.996 | In-Between | 0.925 | Likely Pathogenic | Ambiguous | 3.03 | Destabilizing | 0.1 | 2.87 | Destabilizing | 2.95 | Destabilizing | 0.93 | Ambiguous | 0.407 | Likely Benign | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.75 | Pathogenic | 0.04 | Affected | 3.37 | 25 | 0.4617 | 0.2637 | -3 | -2 | 0.5 | -76.10 | 200.1 | 77.8 | 0.0 | 0.0 | -0.2 | 0.1 | Potentially Pathogenic | The phenol ring of Tyr342, located at the end of an anti-parallel β sheet strand (res. Gly341-Pro349), faces outward in the C2 domain. In the WT simulations, the phenol ring of Tyr342 contributes to a triple tyrosine stack (Tyr342, Tyr328, and Tyr281) that links together three anti-parallel β sheet strands. Additionally, it shields Gly344 from the solvent, reducing its exposure and providing stability for the β-sandwich. This motif also contributes to a twist formation in the β sheet.In the variant simulations, the Ser342 side chain cannot participate in the stack formation. Instead, the hydroxyl group of the Ser342 side chain forms a hydrogen bond with the imidazole ring of His326 in a neighboring β strand (res. Ala322-Asp330). This disrupts the formation of a hydrogen bond between His326 and the carboxylate group of the Glu283 side chain from another β strand (res. Arg279-Cys285). Although these changes in surface interactions could weaken the characteristic twist that strengthens the β sheet fold, no major structural effects are observed in the variant simulations. The residue swap could also affect the SynGAP-membrane association, as the hydroxyl group of Ser342 could form hydrogen bonds with membrane-facing loop residues. However, this phenomenon cannot be addressed using solvent-only simulations. | |||||||||||||||||
| c.1091C>A | P364H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P364H is reported in gnomAD (ID 6‑33437996‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic. The protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with 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 | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | 6-33437996-C-A | -10.744 | Likely Pathogenic | 0.632 | Likely Pathogenic | Likely Benign | 1.65 | Ambiguous | 0.9 | 0.25 | Likely Benign | 0.95 | Ambiguous | 0.77 | Ambiguous | 0.407 | Likely Benign | -6.96 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.55 | Pathogenic | 0.02 | Affected | 3.39 | 20 | 0.1800 | 0.4584 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||
| c.1943T>A | F648Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F648Y is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33441202‑T‑A). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. 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 balance of evidence favors a pathogenic classification for F648Y. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | 6-33441202-T-A | 4 | 2.48e-6 | -8.632 | Likely Pathogenic | 0.889 | Likely Pathogenic | Ambiguous | 0.74 | Ambiguous | 0.1 | 0.94 | Ambiguous | 0.84 | Ambiguous | 1.11 | Destabilizing | 0.407 | Likely Benign | -2.99 | Deleterious | 0.984 | Probably Damaging | 0.913 | Probably Damaging | 3.41 | Benign | 0.11 | Tolerated | 3.37 | 30 | 0.1307 | 0.1396 | 3 | 7 | -4.1 | 16.00 | ||||||||||||||||||||||||
| c.1997A>C | E666A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E666A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: FoldX (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive because FoldX is Uncertain while Rosetta is Benign. Overall, the majority of available predictions (six pathogenic vs. five benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, 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 Pathogenic | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -11.122 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.1 | 0.18 | Likely Benign | 0.38 | Likely Benign | 0.50 | Likely Benign | 0.407 | Likely Benign | -5.15 | Deleterious | 0.992 | Probably Damaging | 0.863 | Possibly Damaging | 3.45 | Benign | 0.07 | Tolerated | 0.3950 | 0.4878 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.3413C>T | S1138F 2D  AIThe SynGAP1 missense variant S1138F is not reported in ClinVar and is present in gnomAD (ID 6‑33444448‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The high‑accuracy AlphaMissense‑Optimized score is benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (benign), FATHMM (benign), and PROVEAN (pathogenic), resolves to benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates a benign 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. | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | 6-33444448-C-T | 1 | 6.20e-7 | -6.298 | Likely Benign | 0.379 | Ambiguous | Likely Benign | 0.407 | Likely Benign | -2.88 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 4 | 0.0991 | 0.5623 | -2 | -3 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||
| c.3605T>C | I1202T 2D AIThe SynGAP1 missense variant I1202T is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus likewise indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence points to the variant being most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.529623 | Disordered | 0.510422 | Binding | 0.874 | 0.593 | 0.250 | -9.433 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.407 | Likely Benign | -3.96 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.81 | Pathogenic | 0.01 | Affected | 0.1118 | 0.0846 | 0 | -1 | -5.2 | -12.05 | ||||||||||||||||||||||||||||||||||||||
| c.3659A>C | E1220A 2D AIThe SynGAP1 missense variant E1220A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus likewise indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence from multiple in silico predictors indicates that E1220A 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 | Coiled-coil | 0.703578 | Disordered | 0.444845 | Uncertain | 0.881 | 0.551 | 0.375 | -12.798 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.407 | Likely Benign | -5.12 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.62 | Pathogenic | 0.00 | Affected | 0.3345 | 0.4105 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3665G>C | R1222T 2D AIThe SynGAP1 missense variant R1222T is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and SIFT, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that R1222T is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -11.164 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.407 | Likely Benign | -4.39 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.48 | Pathogenic | 0.13 | Tolerated | 0.1550 | 0.2851 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||
| c.1072T>G | F358V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F358V 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and ESM1b. Five tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F358V, 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 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -9.021 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 1.42 | Ambiguous | 0.2 | 1.68 | Ambiguous | 1.55 | Ambiguous | 0.93 | Ambiguous | 0.408 | Likely Benign | -5.32 | Deleterious | 0.993 | Probably Damaging | 0.968 | Probably Damaging | 4.09 | Benign | 0.18 | Tolerated | 0.2222 | 0.2978 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1422C>A | D474E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D474E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas a separate group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools are uncertain: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, but the high‑accuracy tools provide conflicting evidence. Thus, the variant is most likely pathogenic based on the current computational predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -7.079 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.15 | Likely Benign | 0.10 | Likely Benign | 0.408 | Likely Benign | -3.01 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -1.11 | Pathogenic | 0.20 | Tolerated | 0.1233 | 0.4287 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1422C>G | D474E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D474E is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT, while those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Two tools—AlphaMissense‑Optimized and ESM1b—return uncertain results. High‑accuracy assessments show SGM‑Consensus predicting a likely pathogenic outcome, AlphaMissense‑Optimized remaining uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of consensus tools lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -7.079 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.15 | Likely Benign | 0.10 | Likely Benign | 0.408 | Likely Benign | -3.01 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -1.11 | Pathogenic | 0.20 | Tolerated | 0.1233 | 0.4287 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.3455A>T | E1152V 2D AIThe SynGAP1 missense variant E1152V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. 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 because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.741537 | Disordered | 0.811118 | Binding | 0.395 | 0.846 | 0.500 | -3.304 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.408 | Likely Benign | -4.65 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1247 | 0.6384 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.3809A>T | E1270V 2D AIThe SynGAP1 missense variant E1270V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus agrees. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that E1270V 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 | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -13.293 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.408 | Likely Benign | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.0570 | 0.6461 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.3181G>T | G1061C 2D AIThe SynGAP1 missense variant G1061C is listed in ClinVar (ID 536997.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443733‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence (six benign vs. four pathogenic predictions) and the two high‑accuracy tools support a benign classification. This conclusion does not contradict the ClinVar status, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | Conflicting | 2 | 6-33443733-G-T | 6 | 3.73e-6 | -9.511 | Likely Pathogenic | 0.119 | Likely Benign | Likely Benign | 0.409 | Likely Benign | -1.46 | Neutral | 0.938 | Possibly Damaging | 0.665 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 4.32 | 2 | 0.1283 | 0.4227 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||
| c.3583G>A | V1195M 2D  AIThe SynGAP1 V1195M missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools split evenly: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is “Uncertain,” SGM‑Consensus (majority vote) is benign, and Foldetta stability analysis is unavailable. Overall, the majority of evidence—including the SGM‑Consensus and the balance of individual predictors—leans toward a benign effect. This conclusion 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 Benign | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -3.564 | Likely Benign | 0.944 | Likely Pathogenic | Ambiguous | 0.409 | Likely Benign | -1.01 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 5.46 | Benign | 0.04 | Affected | 0.0589 | 0.3421 | 2 | 1 | -2.3 | 32.06 | ||||||||||||||||||||||||||||||||||||||
| c.976C>A | H326N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326N has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and SIFT, whereas a majority (seven) predict a pathogenic outcome: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence points to a pathogenic impact for H326N, 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 | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -8.914 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.81 | Ambiguous | 0.2 | 1.48 | Ambiguous | 1.15 | Ambiguous | 0.97 | Ambiguous | 0.409 | Likely Benign | -5.63 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.95 | Pathogenic | 0.11 | Tolerated | 0.1929 | 0.2552 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.1017G>C | K339N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339N 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 premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of evidence points to a pathogenic impact for K339N, 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 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -11.117 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.0 | 0.35 | Likely Benign | 0.28 | Likely Benign | 0.00 | Likely Benign | 0.410 | Likely Benign | -3.88 | Deleterious | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 1.91 | Pathogenic | 0.02 | Affected | 0.3224 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1017G>T | K339N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K339N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, 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 show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact for K339N, and this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -11.117 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.0 | 0.35 | Likely Benign | 0.28 | Likely Benign | 0.00 | Likely Benign | 0.410 | Likely Benign | -3.88 | Deleterious | 0.991 | Probably Damaging | 0.864 | Possibly Damaging | 1.91 | Pathogenic | 0.02 | Affected | 0.3224 | 0.1158 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1507C>G | Q503E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and Rosetta. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Overall, the majority of available predictions favor a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -7.909 | In-Between | 0.146 | Likely Benign | Likely Benign | 0.51 | Ambiguous | 0.1 | 2.11 | Destabilizing | 1.31 | Ambiguous | 0.85 | Ambiguous | 0.410 | Likely Benign | -2.21 | Neutral | 0.931 | Possibly Damaging | 0.500 | Possibly Damaging | -1.43 | Pathogenic | 0.17 | Tolerated | 0.1168 | 0.1508 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.2135G>T | G712V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G712V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Two tools report uncertainty: 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 (combining FoldX‑MD and Rosetta outputs) as 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 entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -10.466 | Likely Pathogenic | 0.877 | Likely Pathogenic | Ambiguous | 3.79 | Destabilizing | 0.0 | 6.18 | Destabilizing | 4.99 | Destabilizing | 0.79 | Ambiguous | 0.410 | Likely Benign | -7.55 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.00 | Affected | 0.1395 | 0.3712 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.3166G>C | G1056R 2D AIThe SynGAP1 missense variant G1056R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors a pathogenic outcome, and Foldetta data are unavailable. Overall, the majority of conventional predictors indicate a benign impact, whereas the SGM Consensus suggests pathogenicity. Given the preponderance of benign predictions and the lack of ClinVar evidence, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -9.358 | Likely Pathogenic | 0.390 | Ambiguous | Likely Benign | 0.410 | Likely Benign | 0.12 | Neutral | 0.011 | Benign | 0.010 | Benign | 1.83 | Pathogenic | 0.13 | Tolerated | 0.1127 | 0.4533 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3532T>A | Y1178N 2D  AIThe SynGAP1 missense variant Y1178N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools are divided: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, 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 | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -2.125 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.410 | Likely Benign | -1.18 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 5.50 | Benign | 0.09 | Tolerated | 0.2456 | 0.0341 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.3743T>C | L1248P 2D AIThe SynGAP1 missense variant L1248P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus agrees. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence 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 | Coiled-coil | 0.834292 | Disordered | 0.371716 | Uncertain | 0.880 | 0.562 | 0.625 | -14.647 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.410 | Likely Benign | -5.45 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | 0.3596 | 0.0848 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| c.548A>C | H183P 2D AIThe SynGAP1 missense variant H183P 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, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized also predicts Pathogenic, while the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic impact, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -18.527 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.410 | Likely Benign | -7.18 | Deleterious | 0.838 | Possibly Damaging | 0.276 | Benign | 3.79 | Benign | 0.01 | Affected | 0.2143 | 0.3712 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.593T>G | L198R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from multiple in‑silico predictors indicates that 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 | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -15.992 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.2 | 1.56 | Ambiguous | 1.15 | Ambiguous | 0.69 | Ambiguous | 0.410 | Likely Benign | -4.98 | Deleterious | 0.982 | Probably Damaging | 0.648 | Possibly Damaging | 3.34 | Benign | 0.00 | Affected | 0.1180 | 0.0719 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||
| c.823C>G | P275A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275A is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437728‑C‑G). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is uncertain. Consequently, the overall evidence leans toward a benign interpretation, with no ClinVar record to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | 6-33437728-C-G | 1 | 6.20e-7 | -6.137 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 1.87 | Ambiguous | 0.2 | 1.11 | Ambiguous | 1.49 | Ambiguous | 0.50 | Likely Benign | 0.410 | Likely Benign | -4.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.32 | Tolerated | 3.38 | 19 | 0.3475 | 0.3243 | -1 | 1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.1186G>T | G396C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396C 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; premPS is uncertain. The high‑accuracy consensus methods give a mixed signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of individual predictors and the SGM‑Consensus lean toward a benign interpretation, and the two high‑accuracy tools that are available also favor benign over pathogenic. Therefore, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -5.459 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 2.15 | Destabilizing | 0.7 | 2.52 | Destabilizing | 2.34 | Destabilizing | 0.59 | Ambiguous | 0.411 | Likely Benign | -3.00 | Deleterious | 0.983 | Probably Damaging | 0.533 | Possibly Damaging | 3.89 | Benign | 0.08 | Tolerated | 0.1181 | 0.4541 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1769G>A | S590N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590N is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of other in silico predictors (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) indicate a pathogenic or likely pathogenic impact. FoldX and Foldetta, which assess protein‑folding stability, return uncertain results and are therefore not considered evidence for either outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of pathogenic predictions strongly suggests that S590N is most likely pathogenic, a conclusion that is consistent with the absence of ClinVar annotation and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -15.149 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 1.27 | Ambiguous | 0.1 | 2.10 | Destabilizing | 1.69 | Ambiguous | 1.48 | Destabilizing | 0.411 | Likely Benign | -2.96 | Deleterious | 0.921 | Possibly Damaging | 0.598 | Possibly Damaging | 3.14 | Benign | 0.01 | Affected | 0.1254 | 0.4202 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||
| c.2039A>G | E680G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E680G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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 tools lean toward a pathogenic effect, with high‑accuracy methods split but tipping toward pathogenicity. The variant’s status in ClinVar is unknown, so there is no contradiction between the predictions and existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -11.396 | Likely Pathogenic | 0.743 | Likely Pathogenic | Likely Benign | 0.67 | Ambiguous | 0.2 | 0.11 | Likely Benign | 0.39 | Likely Benign | 0.44 | Likely Benign | 0.411 | Likely Benign | -5.48 | Deleterious | 0.998 | Probably Damaging | 0.739 | Possibly Damaging | 3.47 | Benign | 0.01 | Affected | 0.2708 | 0.6228 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.3527A>C | E1176A 2D AIThe SynGAP1 E1176A missense change is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors shows a split: benign‑oriented tools (REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all indicate a benign effect, whereas pathogenic‑oriented tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default) predict a deleterious impact. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the Foldetta stability assessment is unavailable. Taking the overall evidence together, the variant is most likely benign; this assessment does not conflict with ClinVar, which contains no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.538167 | Disordered | 0.572075 | Binding | 0.525 | 0.715 | 0.250 | -3.164 | Likely Benign | 0.909 | Likely Pathogenic | Ambiguous | 0.411 | Likely Benign | -1.95 | Neutral | 0.995 | Probably Damaging | 0.924 | Probably Damaging | 5.55 | Benign | 0.19 | Tolerated | 0.3160 | 0.5889 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.623C>A | P208Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P208Q 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. The majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta. Two tools give uncertain results (AlphaMissense‑Optimized and Rosetta) and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Pathogenic, reinforcing a deleterious prediction. Overall, the evidence strongly favors a pathogenic classification, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | -9.746 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 3.30 | Destabilizing | 0.7 | 0.75 | Ambiguous | 2.03 | Destabilizing | 1.23 | Destabilizing | 0.411 | Likely Benign | -6.78 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.78 | Benign | 0.00 | Affected | 0.1570 | 0.4663 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||
| c.1067G>T | R356L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R356L is not reported in ClinVar and is present in gnomAD (ID 6‑33437972‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, and Foldetta, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence points to a pathogenic effect for R356L, and 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 | C2 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | 6-33437972-G-T | -13.957 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | -0.04 | Likely Benign | 0.1 | -0.57 | Ambiguous | -0.31 | Likely Benign | 0.68 | Ambiguous | 0.412 | Likely Benign | -6.20 | Deleterious | 0.993 | Probably Damaging | 0.982 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 3.39 | 22 | 0.2110 | 0.5242 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||||
| c.1402A>C | M468L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments—all available—show benign predictions: AlphaMissense‑Optimized (Benign), SGM‑Consensus (Likely Benign), and Foldetta (Benign). Based on the overall consensus of the majority of tools and the high‑accuracy predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -6.886 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.43 | Likely Benign | 0.1 | -0.38 | Likely Benign | 0.03 | Likely Benign | -0.35 | Likely Benign | 0.412 | Likely Benign | 0.19 | Neutral | 0.359 | Benign | 0.654 | Possibly Damaging | -0.73 | Pathogenic | 1.00 | Tolerated | 0.1564 | 0.4408 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1402A>T | M468L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign outcome. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | -6.886 | Likely Benign | 0.290 | Likely Benign | Likely Benign | 0.43 | Likely Benign | 0.1 | -0.38 | Likely Benign | 0.03 | Likely Benign | -0.35 | Likely Benign | 0.412 | Likely Benign | 0.19 | Neutral | 0.359 | Benign | 0.654 | Possibly Damaging | -0.73 | Pathogenic | 1.00 | Tolerated | 0.1564 | 0.4408 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.1873C>A | L625I 2D AIThe SynGAP1 missense variant L625I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas a majority of tools (premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Consequently, the overall evidence leans toward pathogenicity, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -11.713 | Likely Pathogenic | 0.866 | Likely Pathogenic | Ambiguous | 0.75 | Ambiguous | 0.6 | 0.72 | Ambiguous | 0.74 | Ambiguous | 1.09 | Destabilizing | 0.412 | Likely Benign | -1.96 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 0.0864 | 0.3588 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.3631A>G | M1211V 2D  AIThe SynGAP1 missense variant M1211V is listed in ClinVar as Benign (ClinVar ID 3674914.0) and is present in gnomAD (ID 6‑33446623‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | Benign | 1 | 6-33446623-A-G | 3 | 1.86e-6 | -2.101 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.412 | Likely Benign | -0.29 | Neutral | 0.932 | Possibly Damaging | 0.949 | Probably Damaging | 5.43 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2676 | 0.2720 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||
| c.670A>T | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S 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, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give 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) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. 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 Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | 0.412 | Likely Benign | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 0.3498 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1358A>T | H453L 2D 3DClick to see structure in 3D Viewer AISynGAP1 H453L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, premPS, SIFT, FATHMM, and the protein‑folding stability method Foldetta; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments indicate that AlphaMissense‑Optimized is uncertain, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the predictions are split, with a slight edge toward pathogenicity from the consensus and high‑accuracy tools, but the presence of several benign calls and the uncertainty of AlphaMissense‑Optimized temper this conclusion. Thus, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -10.438 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | -0.59 | Ambiguous | 0.1 | 0.04 | Likely Benign | -0.28 | Likely Benign | 0.31 | Likely Benign | 0.413 | Likely Benign | -10.87 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.45 | Benign | 0.11 | Tolerated | 0.0841 | 0.4964 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.1562A>T | E521V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E521V missense change 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, 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 AlphaMissense‑Optimized score is pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact for E521V, 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 | 0.086953 | Structured | 0.062387 | Uncertain | 0.865 | 0.349 | 0.000 | -10.297 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 0.1 | 0.49 | Likely Benign | 0.40 | Likely Benign | 0.21 | Likely Benign | 0.413 | Likely Benign | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.996 | Probably Damaging | 3.26 | Benign | 0.05 | Affected | 0.0913 | 0.7104 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.3184G>C | G1062R 2D AIThe SynGAP1 missense variant G1062R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicating a likely benign outcome, and Foldetta results are 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 | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -6.933 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.413 | Likely Benign | -0.34 | Neutral | 0.797 | Possibly Damaging | 0.139 | Benign | 4.10 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1013 | 0.4342 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.3521A>C | E1174A 2D AIThe SynGAP1 missense variant E1174A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available, so they do not influence the conclusion. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | -3.512 | Likely Benign | 0.737 | Likely Pathogenic | Likely Benign | 0.413 | Likely Benign | -2.24 | Neutral | 0.790 | Possibly Damaging | 0.353 | Benign | 5.44 | Benign | 0.02 | Affected | 0.3462 | 0.5889 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3653A>G | E1218G 2D AIThe SynGAP1 missense variant E1218G 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 ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely pathogenic. AlphaMissense‑Optimized returns an uncertain result, and no Foldetta (FoldX‑MD/Rosetta) stability assessment is available. Based on the collective evidence, 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 | Coiled-coil | 0.595080 | Disordered | 0.483050 | Uncertain | 0.898 | 0.565 | 0.375 | -5.595 | Likely Benign | 0.864 | Likely Pathogenic | Ambiguous | 0.413 | Likely Benign | -5.61 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.2496 | 0.4095 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.3709T>A | Y1237N 2D AIThe SynGAP1 missense variant Y1237N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.653063 | Disordered | 0.563444 | Binding | 0.842 | 0.535 | 0.125 | -10.505 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.413 | Likely Benign | -7.18 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.44 | Pathogenic | 0.00 | Affected | 0.2428 | 0.0173 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.3808G>A | E1270K 2D AIThe SynGAP1 missense variant E1270K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence indicates that E1270K 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 | Coiled-coil | 0.490133 | Structured | 0.771865 | Binding | 0.805 | 0.659 | 0.250 | -12.549 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.413 | Likely Benign | -3.37 | Deleterious | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.07 | Pathogenic | 0.00 | Affected | 0.1780 | 0.6276 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.637A>G | I213V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213V missense variant is not reported in ClinVar (no ClinVar ID) 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‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, 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 benign, while Foldetta’s stability analysis is uncertain. Overall, the evidence strongly favors a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -6.133 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.67 | Ambiguous | 0.2 | 0.58 | Ambiguous | 0.63 | Ambiguous | 0.47 | Likely Benign | 0.413 | Likely Benign | -0.69 | Neutral | 0.128 | Benign | 0.048 | Benign | 5.82 | Benign | 0.10 | Tolerated | 0.1008 | 0.2959 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1088A>G | Y363C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y363C is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33437993‑A‑G). Prediction tools cluster into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—indicate pathogenicity. High‑accuracy assessments further support this: 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) also predicts pathogenic. With the 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 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | 6-33437993-A-G | 1 | 7.13e-7 | -9.059 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 2.21 | Destabilizing | 0.1 | 3.96 | Destabilizing | 3.09 | Destabilizing | 2.05 | Destabilizing | 0.414 | Likely Benign | -8.07 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 3.39 | 24 | 0.3759 | 0.3463 | -2 | 0 | 3.8 | -60.04 | ||||||||||||||||||||||||
| 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.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.1396T>A | S466T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence points to a benign impact. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -5.488 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.2 | -1.02 | Ambiguous | -0.36 | Likely Benign | -0.65 | Ambiguous | 0.414 | Likely Benign | 1.05 | Neutral | 0.740 | Possibly Damaging | 0.872 | Possibly Damaging | -1.51 | Pathogenic | 1.00 | Tolerated | 0.0928 | 0.5152 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1494G>T | M498I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | 0.414 | Likely Benign | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.1184 | 0.2537 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1726T>A | C576S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C576S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions from REVEL and FATHMM, while the majority of other in silico methods (premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. FoldX and Rosetta give uncertain stability changes, and Foldetta likewise reports no definitive effect. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic. Foldetta remains inconclusive. Overall, the preponderance of evidence from multiple pathogenic‑oriented tools and the high‑accuracy predictions indicates that C576S is most likely pathogenic, which is consistent with the absence of a ClinVar entry and gnomAD data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.017684 | Uncertain | 0.913 | 0.245 | 0.000 | -10.474 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.77 | Ambiguous | 0.1 | 1.57 | Ambiguous | 1.17 | Ambiguous | 1.61 | Destabilizing | 0.414 | Likely Benign | -8.91 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.40 | Benign | 0.02 | Affected | 0.4968 | 0.1464 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1772C>A | A591D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A591D 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 evaluated algorithms (AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, premPS, FoldX‑MD, Rosetta, Foldetta, and the SGM Consensus) uniformly predict a pathogenic or likely pathogenic outcome; FoldX‑MD is uncertain but does not counter the overall trend. 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) also predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign 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 | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | -14.747 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.2 | 2.77 | Destabilizing | 2.16 | Destabilizing | 1.40 | Destabilizing | 0.414 | Likely Benign | -5.02 | Deleterious | 0.919 | Possibly Damaging | 0.495 | Possibly Damaging | 3.42 | Benign | 0.00 | Affected | 0.1550 | 0.1741 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.2777C>G | S926C 2D  AIThe SynGAP1 missense variant S926C 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, ESM1b, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of predictions lean toward pathogenicity, with the high‑accuracy AlphaMissense‑Optimized result providing a conflicting benign signal. Thus, the variant is most likely pathogenic based on the collective evidence, 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.546 | Likely Benign | 0.680 | Likely Pathogenic | Likely Benign | 0.414 | Likely Benign | -3.81 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0815 | 0.5487 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.3489C>A | H1163Q 2D  AIThe SynGAP1 missense variant H1163Q 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, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H1163Q. This conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.970 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | -1.41 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.43 | Benign | 0.58 | Tolerated | 0.1445 | 0.3424 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3489C>G | H1163Q 2D AIThe SynGAP1 missense variant H1163Q 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, ESM1b, and FATHMM. Tools that predict a pathogenic effect 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, indicates a likely benign outcome. AlphaMissense‑Optimized is uncertain, and no Foldetta (FoldX‑MD/Rosetta stability) result is available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar reporting and gnomAD presence, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.970 | Likely Benign | 0.899 | Likely Pathogenic | Ambiguous | 0.414 | Likely Benign | -1.41 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.43 | Benign | 0.58 | Tolerated | 0.1445 | 0.3424 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||||
| c.499G>T | D167Y 2D AIThe SynGAP1 missense variant D167Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and FATHMM, whereas the remaining eight predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized—and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points to a pathogenic impact for D167Y, and this conclusion is not contradicted by any ClinVar annotation, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -14.228 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.414 | Likely Benign | -4.23 | Deleterious | 0.898 | Possibly Damaging | 0.557 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.0493 | 0.6358 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.933C>A | H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. The high‑accuracy consensus methods give mixed signals: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, more tools (seven) predict pathogenicity than benign (four), and the SGM Consensus supports a pathogenic classification, while Foldetta offers a contrary benign prediction. The variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -8.656 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.27 | Likely Benign | 0.92 | Ambiguous | 0.414 | Likely Benign | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.03 | Affected | 0.1490 | 0.3775 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.933C>G | H311Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311Q 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, Rosetta, and Foldetta. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, 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 Benign. With seven pathogenic versus four benign predictions, the overall consensus leans toward pathogenicity. 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 | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -8.656 | Likely Pathogenic | 0.792 | Likely Pathogenic | Ambiguous | 0.15 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.27 | Likely Benign | 0.92 | Ambiguous | 0.414 | Likely Benign | -5.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.03 | Affected | 0.1490 | 0.3775 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| 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.1553A>G | Y518C 2D AIThe SynGAP1 missense variant Y518C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; and uncertain results from Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus indicates likely pathogenic, and Foldetta predicts pathogenic folding instability. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | -9.813 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 2.99 | Destabilizing | 0.9 | 1.70 | Ambiguous | 2.35 | Destabilizing | 0.69 | Ambiguous | 0.415 | Likely Benign | -8.35 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.16 | Tolerated | 0.2905 | 0.1128 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.3432G>C | L1144F 2D  AIThe SynGAP1 missense variant L1144F 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -4.375 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.415 | Likely Benign | -1.71 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 5.69 | Benign | 0.04 | Affected | 0.0685 | 0.3283 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3432G>T | L1144F 2D AIThe SynGAP1 missense variant L1144F is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the aggregate evidence, the variant is most likely benign. This assessment does not contradict ClinVar status, as no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.950334 | Disordered | 0.726803 | Binding | 0.277 | 0.840 | 1.000 | -4.375 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.415 | Likely Benign | -1.71 | Neutral | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 5.69 | Benign | 0.04 | Affected | 0.0685 | 0.3283 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3658G>A | E1220K 2D AIThe SynGAP1 missense variant E1220K is listed in gnomAD (6‑33446650‑G‑A) but has no ClinVar entry. Prediction tools that agree on benign impact include REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that E1220K 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 | Coiled-coil | 0.703578 | Disordered | 0.444845 | Uncertain | 0.881 | 0.551 | 0.375 | 6-33446650-G-A | 1 | 6.20e-7 | -12.478 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.415 | Likely Benign | -3.46 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.63 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1862 | 0.4046 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||
| c.1091C>G | P364R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 P364R missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; Foldetta’s stability analysis is uncertain. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate 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 | C2 | 0.390993 | Structured | 0.439474 | Uncertain | 0.942 | 0.590 | 0.250 | -12.652 | Likely Pathogenic | 0.715 | Likely Pathogenic | Likely Benign | 0.95 | Ambiguous | 0.7 | 0.88 | Ambiguous | 0.92 | Ambiguous | 0.73 | Ambiguous | 0.416 | Likely Benign | -6.76 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.57 | Pathogenic | 0.12 | Tolerated | 0.1520 | 0.3977 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| 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.1867C>G | L623V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and AlphaMissense‑Optimized give uncertain results. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic, and AlphaMissense‑Optimized remains uncertain. 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 | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -12.802 | Likely Pathogenic | 0.896 | Likely Pathogenic | Ambiguous | 3.96 | Destabilizing | 0.3 | 1.84 | Ambiguous | 2.90 | Destabilizing | 1.45 | Destabilizing | 0.416 | Likely Benign | -2.99 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.60 | Pathogenic | 0.01 | Affected | 0.1653 | 0.3588 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.3392C>G | P1131R 2D AIThe SynGAP1 P1131R missense variant has no ClinVar record and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, SIFT, 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 due to a 2‑to‑2 split, and Foldetta data are unavailable. With five benign versus four pathogenic calls and a benign result from the most accurate tool, the variant is most likely benign. 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. | 0.919029 | Disordered | 0.855155 | Binding | 0.360 | 0.899 | 0.750 | -3.792 | Likely Benign | 0.702 | Likely Pathogenic | Likely Benign | 0.416 | Likely Benign | -2.58 | Deleterious | 0.918 | Possibly Damaging | 0.420 | Benign | 5.26 | Benign | 0.00 | Affected | 0.1252 | 0.4010 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.861T>A | D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate 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 | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -5.250 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.35 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.50 | Likely Benign | 0.416 | Likely Benign | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.1541 | 0.7833 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.861T>G | D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate 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 | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -5.250 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.35 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.50 | Likely Benign | 0.416 | Likely Benign | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.1541 | 0.7833 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1295G>C | C432S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools (SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification for C432S, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -8.229 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.52 | Destabilizing | 0.417 | Likely Benign | -9.55 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.12 | Tolerated | 0.4262 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1300G>T | V434F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434F is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM‑Consensus predicts pathogenic; Foldetta predicts pathogenic. All predictions are available and none are inconclusive. Based on the overall distribution of predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -12.553 | Likely Pathogenic | 0.672 | Likely Pathogenic | Likely Benign | 3.64 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.46 | Destabilizing | 0.27 | Likely Benign | 0.417 | Likely Benign | -3.93 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.44 | Benign | 0.04 | Affected | 0.0596 | 0.3391 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1730C>T | A577V 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A577V is catalogued in gnomAD (ID 6‑33440782‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign; the SGM consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports benign. No prediction or stability result is missing or inconclusive in these key analyses. Consequently, 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. | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | 6-33440782-C-T | 2 | 1.24e-6 | -4.265 | Likely Benign | 0.432 | Ambiguous | Likely Benign | 0.69 | Ambiguous | 0.1 | 0.00 | Likely Benign | 0.35 | Likely Benign | 0.16 | Likely Benign | 0.417 | Likely Benign | -2.11 | Neutral | 0.997 | Probably Damaging | 0.976 | Probably Damaging | -1.32 | Pathogenic | 0.26 | Tolerated | 3.37 | 34 | 0.1278 | 0.4790 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||
| c.2038G>A | E680K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E680K 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 HumVar, and FATHMM. Those that predict a pathogenic effect are SIFT, PROVEAN, polyPhen‑2 HumDiv, 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 Benign. With a majority of individual tools and the SGM‑Consensus indicating pathogenicity, 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 | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -12.728 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | -0.10 | Likely Benign | 0.4 | -0.15 | Likely Benign | -0.13 | Likely Benign | 0.33 | Likely Benign | 0.417 | Likely Benign | -3.54 | Deleterious | 0.959 | Probably Damaging | 0.411 | Benign | 3.49 | Benign | 0.02 | Affected | 0.3048 | 0.7553 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.2162T>C | I721T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721T is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that indicate a benign effect include only REVEL. All other evaluated tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote) yields Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts Pathogenic. No prediction or folding result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -10.374 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.73 | Destabilizing | 0.0 | 2.56 | Destabilizing | 2.65 | Destabilizing | 2.11 | Destabilizing | 0.417 | Likely Benign | -4.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.22 | Pathogenic | 0.00 | Affected | 0.0918 | 0.1019 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.3497C>A | A1166D 2D AIThe SynGAP1 missense variant A1166D 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, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (five benign vs. four pathogenic) and the consensus score lean toward a benign interpretation, with no conflict with ClinVar status. Thus, the variant is most likely benign, although the AlphaMissense‑Optimized prediction introduces some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -4.204 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.417 | Likely Benign | -1.56 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 5.29 | Benign | 0.42 | Tolerated | 0.1709 | 0.2104 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.3707A>C | Q1236P 2D  AIThe SynGAP1 missense variant Q1236P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a pathogenic effect, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.680603 | Disordered | 0.567914 | Binding | 0.883 | 0.537 | 0.125 | -10.868 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.417 | Likely Benign | -3.16 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.1768 | 0.3847 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||
| c.3872T>C | L1291P 2D AIThe SynGAP1 missense variant L1291P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, five tools predict pathogenicity while four predict benignity, giving a slight tilt toward a pathogenic interpretation. Because there is no ClinVar assertion, this prediction does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -3.322 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.417 | Likely Benign | -4.32 | Deleterious | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.48 | Pathogenic | 0.01 | Affected | 0.3078 | 0.2162 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| 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.1494G>A | M498I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | 0.418 | Likely Benign | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.1184 | 0.2537 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1494G>C | M498I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M498I has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, SIFT, FATHMM, and AlphaMissense‑Default. Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions lean toward a benign impact, and this is not contradicted by ClinVar status, which lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -4.796 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 2.56 | Destabilizing | 0.3 | 1.65 | Ambiguous | 2.11 | Destabilizing | 0.88 | Ambiguous | 0.418 | Likely Benign | -1.09 | Neutral | 0.018 | Benign | 0.012 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.1184 | 0.2537 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.1700A>C | E567A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E567A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, SIFT, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Four tools (Foldetta, premPS, Rosetta, AlphaMissense‑Optimized) yield 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 has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.021816 | Structured | 0.051008 | Uncertain | 0.916 | 0.234 | 0.000 | -12.854 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.1 | 1.79 | Ambiguous | 1.11 | Ambiguous | 0.63 | Ambiguous | 0.418 | Likely Benign | -5.74 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.43 | Benign | 0.17 | Tolerated | 0.3170 | 0.5189 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1901C>G | A634G 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A634G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls are made by Rosetta, premPS, PROVEAN, both polyPhen‑2 versions, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta give uncertain results. High‑accuracy assessments indicate AlphaMissense‑Optimized predicts benign, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta remains uncertain. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic interpretation. Therefore, 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 | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -10.685 | Likely Pathogenic | 0.613 | Likely Pathogenic | Likely Benign | 1.63 | Ambiguous | 0.1 | 2.27 | Destabilizing | 1.95 | Ambiguous | 1.09 | Destabilizing | 0.418 | Likely Benign | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.990 | Probably Damaging | 2.69 | Benign | 0.15 | Tolerated | 0.2182 | 0.3187 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.2183C>G | P728R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P728R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FoldX, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further indicate a likely pathogenic status from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and an uncertain outcome from Foldetta (combining FoldX‑MD and Rosetta). AlphaMissense‑Optimized also remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, 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 | 0.632174 | Disordered | 0.434760 | Uncertain | 0.725 | 0.567 | 0.625 | -10.309 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.52 | Ambiguous | 0.70 | Ambiguous | 0.418 | Likely Benign | -7.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.1728 | 0.2865 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||
| c.3131C>T | P1044L 2D AIThe SynGAP1 missense variant P1044L is not represented in ClinVar (no ClinVar ID) and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized indicates benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective predictions, the 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 | 0.979741 | Disordered | 0.952126 | Binding | 0.331 | 0.855 | 0.750 | -4.327 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.418 | Likely Benign | -1.64 | Neutral | 0.411 | Benign | 0.187 | Benign | 5.43 | Benign | 0.15 | Tolerated | 0.2264 | 0.6586 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3409C>G | H1137D 2D AIThe SynGAP1 missense variant H1137D is not reported in ClinVar and has no allele in gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Pathogenicity is suggested only by polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for H1137D, 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 | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | -4.934 | Likely Benign | 0.343 | Ambiguous | Likely Benign | 0.418 | Likely Benign | -2.26 | Neutral | 0.802 | Possibly Damaging | 0.430 | Benign | 5.56 | Benign | 0.00 | Affected | 0.2519 | 0.2916 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3529G>C | E1177Q 2D  AIThe SynGAP1 missense variant E1177Q 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, ESM1b, and FATHMM, while those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the evidence is mixed, with an equal split between benign and pathogenic calls; however, the consensus from the high‑accuracy tools leans toward benign. Thus, the variant is most likely benign, 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 Benign | Coiled-coil | 0.541878 | Disordered | 0.566503 | Binding | 0.542 | 0.705 | 0.250 | -3.517 | Likely Benign | 0.812 | Likely Pathogenic | Ambiguous | 0.418 | Likely Benign | -0.95 | Neutral | 0.951 | Possibly Damaging | 0.772 | Possibly Damaging | 5.43 | Benign | 0.04 | Affected | 0.0712 | 0.4265 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3568A>T | S1190C 2D AIThe SynGAP1 missense variant S1190C 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, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. 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 Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, 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 | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | -6.788 | Likely Benign | 0.828 | Likely Pathogenic | Ambiguous | 0.418 | Likely Benign | -1.93 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 5.22 | Benign | 0.07 | Tolerated | 0.1144 | 0.4294 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||
| c.3653A>T | E1218V 2D AISynGAP1 missense variant E1218V is listed in ClinVar with an uncertain significance (ClinVar ID 1015602.0) and is not reported in gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. When the high‑accuracy consensus is considered, AlphaMissense‑Optimized is uncertain, but the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this change. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the ClinVar designation of uncertain significance rather than a benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.595080 | Disordered | 0.483050 | Uncertain | 0.898 | 0.565 | 0.375 | Uncertain | 2 | -5.647 | Likely Benign | 0.936 | Likely Pathogenic | Ambiguous | 0.418 | Likely Benign | -5.68 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.0491 | 0.4120 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||
| c.3677A>C | Q1226P 2D AIThe SynGAP1 missense variant Q1226P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. 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 and the SGM‑Consensus as likely pathogenic; Foldetta’s protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.529623 | Disordered | 0.432206 | Uncertain | 0.850 | 0.547 | 0.250 | -13.176 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.418 | Likely Benign | -4.72 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.75 | Pathogenic | 0.00 | Affected | 0.1829 | 0.4187 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||
| c.790C>A | L264I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L264I is not reported in ClinVar and is present in gnomAD (ID 6‑33437695‑C‑A). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the balance of evidence—six pathogenic versus three benign predictions, a pathogenic SGM Consensus, and an uncertain Foldetta—suggests that 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 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | 6-33437695-C-A | 1 | 6.20e-7 | -10.945 | Likely Pathogenic | 0.638 | Likely Pathogenic | Likely Benign | 1.90 | Ambiguous | 0.5 | 0.84 | Ambiguous | 1.37 | Ambiguous | 0.95 | Ambiguous | 0.418 | Likely Benign | -1.84 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 0.66 | Pathogenic | 0.02 | Affected | 3.38 | 18 | 0.0764 | 0.2630 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||
| c.808G>C | E270Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E270Q missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and premPS, whereas the majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates several high‑accuracy predictors, classifies the variant as Likely Pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized is Uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is Uncertain. Rosetta alone is Uncertain, and Foldetta’s uncertainty reflects limited stability change evidence. Overall, the preponderance of evidence points to a pathogenic effect. 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 | C2 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -11.096 | Likely Pathogenic | 0.886 | Likely Pathogenic | Ambiguous | 0.00 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.50 | Ambiguous | 0.46 | Likely Benign | 0.418 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.65 | Pathogenic | 0.03 | Affected | 0.1044 | 0.4015 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.846T>G | C282W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change C282W is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated predictors—FoldX, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. Uncertain results come only from premPS and Rosetta, which are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely pathogenic status; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. **Thus, the variant is most likely pathogenic based on the collective 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 | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -15.392 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 10.69 | Destabilizing | 1.7 | -1.05 | Ambiguous | 4.82 | Destabilizing | 0.70 | Ambiguous | 0.418 | Likely Benign | -10.11 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.63 | Pathogenic | 0.03 | Affected | 0.1457 | 0.2978 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1043T>G | V348G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a pathogenic effect. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the lack of a benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -12.793 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.2 | 5.70 | Destabilizing | 4.84 | Destabilizing | 2.23 | Destabilizing | 0.419 | Likely Benign | -6.18 | Deleterious | 0.637 | Possibly Damaging | 0.989 | Probably Damaging | 1.56 | Pathogenic | 0.00 | Affected | 0.2229 | 0.2082 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1087T>C | Y363H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y363H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, while the majority of other in silico predictors (Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, Foldetta) indicate a pathogenic impact; FoldX and ESM1b are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for Y363H, 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 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | -7.003 | In-Between | 0.747 | Likely Pathogenic | Likely Benign | 1.75 | Ambiguous | 0.1 | 2.40 | Destabilizing | 2.08 | Destabilizing | 1.04 | Destabilizing | 0.419 | Likely Benign | -4.38 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.56 | Pathogenic | 0.01 | Affected | 0.3267 | 0.2021 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.1124G>C | G375A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect; 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 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -5.986 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 2.52 | Destabilizing | 1.0 | 3.16 | Destabilizing | 2.84 | Destabilizing | -0.09 | Likely Benign | 0.419 | Likely Benign | -0.61 | Neutral | 0.020 | Benign | 0.008 | Benign | 1.33 | Pathogenic | 0.27 | Tolerated | 0.3991 | 0.5242 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1213C>G | R405G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.836 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 3.22 | Destabilizing | 0.5 | 3.26 | Destabilizing | 3.24 | Destabilizing | 1.38 | Destabilizing | 0.419 | Likely Benign | -6.35 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.63 | Benign | 0.01 | Affected | 0.3381 | 0.4139 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1661T>C | V554A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554A 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. All other evaluated predictors—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, 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 | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -9.730 | Likely Pathogenic | 0.870 | Likely Pathogenic | Ambiguous | 2.07 | Destabilizing | 0.1 | 2.34 | Destabilizing | 2.21 | Destabilizing | 2.00 | Destabilizing | 0.419 | Likely Benign | -3.97 | Deleterious | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 3.22 | Benign | 0.02 | Affected | 0.2131 | 0.1633 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1730C>A | A577E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 A577E 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, PROVEAN, and SIFT, whereas those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain; Rosetta and premPS are inconclusive. Overall, the majority of evaluated 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. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | -9.607 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.0 | 0.72 | Ambiguous | 0.51 | Ambiguous | 0.62 | Ambiguous | 0.419 | Likely Benign | -1.91 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.12 | Pathogenic | 0.76 | Tolerated | 0.1487 | 0.1799 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.1978A>G | M660V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M660V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into three groups: benign predictions come from REVEL, SIFT, and FATHMM; pathogenic predictions arise from SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default; the remaining 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 evaluated predictors lean toward a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is available. Thus, based on the current computational evidence, the M660V variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -11.006 | Likely Pathogenic | 0.836 | Likely Pathogenic | Ambiguous | 1.83 | Ambiguous | 0.1 | 0.77 | Ambiguous | 1.30 | Ambiguous | 1.05 | Destabilizing | 0.419 | Likely Benign | -3.99 | Deleterious | 1.000 | Probably Damaging | 0.927 | Probably Damaging | 3.56 | Benign | 0.13 | Tolerated | 0.2614 | 0.2937 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| c.3410A>C | H1137P 2D AIThe SynGAP1 missense variant H1137P is listed in ClinVar as a benign alteration (ClinVar ID 3685596.0) and is present in the gnomAD database (gnomAD ID 6‑33444445‑A‑C). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (derived from the same four high‑accuracy predictors) also indicates benign. No Foldetta (FoldX‑MD/Rosetta stability) result is available for this variant. Overall, the majority of predictions, including the most reliable tools, support a benign classification, which is consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.756488 | Binding | 0.314 | 0.879 | 0.875 | Benign | 1 | 6-33444445-A-C | 12 | 7.44e-6 | -2.098 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.419 | Likely Benign | -1.93 | Neutral | 0.925 | Possibly Damaging | 0.703 | Possibly Damaging | 5.29 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2045 | 0.4501 | -2 | 0 | 1.6 | -40.02 | ||||||||||||||||||||||||||||||||
| c.3674C>A | S1225Y 2D AIThe SynGAP1 missense variant S1225Y 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans toward benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -8.360 | Likely Pathogenic | 0.359 | Ambiguous | Likely Benign | 0.419 | Likely Benign | -2.27 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 5.34 | Benign | 0.04 | Affected | 0.0547 | 0.4691 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.593T>A | L198H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198H 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 predict pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L198H. 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 | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -15.650 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.09 | Ambiguous | 0.2 | 1.04 | Ambiguous | 1.07 | Ambiguous | 0.74 | Ambiguous | 0.419 | Likely Benign | -5.91 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.1057 | 0.0519 | -2 | -3 | -7.0 | 23.98 | ||||||||||||||||||||||||||||||
| c.845G>A | C282Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282Y resides in the C2 domain. ClinVar has no entry for this variant, and it is not listed in gnomAD. Prediction tools that indicate a benign effect are REVEL and premPS. All other evaluated algorithms—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this 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 | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -13.438 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.50 | Destabilizing | 1.1 | 2.91 | Destabilizing | 5.71 | Destabilizing | 0.41 | Likely Benign | 0.419 | Likely Benign | -10.11 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.63 | Pathogenic | 0.00 | Affected | 0.1069 | 0.3089 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.1088A>C | Y363S 2D AIThe SynGAP1 missense variant Y363S 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, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic”; AlphaMissense‑Optimized is classified as “Uncertain”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Taken together, the overwhelming majority of evidence points to a pathogenic effect for Y363S, 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 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | -11.578 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 3.09 | Destabilizing | 0.6 | 3.92 | Destabilizing | 3.51 | Destabilizing | 1.45 | Destabilizing | 0.420 | Likely Benign | -8.04 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 1.56 | Pathogenic | 0.01 | Affected | 0.5750 | 0.4208 | Weaken | -3 | -2 | 0.5 | -76.10 | ||||||||||||||||||||||||||||
| c.1118G>A | G373E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G373E is listed in ClinVar with an Uncertain significance and is not present in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Foldetta, SIFT, and AlphaMissense‑Default. Predictions from Rosetta and ESM1b are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | Uncertain | 1 | -7.281 | In-Between | 0.569 | Likely Pathogenic | Likely Benign | 4.13 | Destabilizing | 3.2 | 0.52 | Ambiguous | 2.33 | Destabilizing | -0.02 | Likely Benign | 0.420 | Likely Benign | -0.69 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.90 | Benign | 0.01 | Affected | 0.1572 | 0.4309 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||
| 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.1750A>C | I584L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I584L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM, while premPS is uncertain. 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 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 | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | -8.266 | Likely Pathogenic | 0.285 | Likely Benign | Likely Benign | -0.18 | Likely Benign | 0.1 | -0.30 | Likely Benign | -0.24 | Likely Benign | 0.84 | Ambiguous | 0.420 | Likely Benign | -1.74 | Neutral | 0.008 | Benign | 0.046 | Benign | -1.23 | Pathogenic | 0.18 | Tolerated | 0.0927 | 0.2817 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1754C>T | A585V 2D AIThe SynGAP1 missense variant A585V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. 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. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.055884 | Uncertain | 0.880 | 0.244 | 0.000 | -10.843 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.95 | Ambiguous | 1.4 | 1.12 | Ambiguous | 1.04 | Ambiguous | 0.51 | Ambiguous | 0.420 | Likely Benign | -3.35 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.27 | Pathogenic | 0.10 | Tolerated | 0.1004 | 0.3496 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.2108T>A | L703H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM‑Consensus itself is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts Pathogenic. Taken together, the overwhelming majority of evidence indicates that 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 | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -12.886 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.0 | 2.29 | Destabilizing | 2.41 | Destabilizing | 1.75 | Destabilizing | 0.420 | Likely Benign | -5.71 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.09 | Benign | 0.00 | Affected | 0.1038 | 0.0288 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.2771C>G | P924R 2D AIThe SynGAP1 missense variant P924R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL and ESM1b, whereas the remaining seven tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. Grouping by consensus, the pathogenic group outweighs the benign group. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta data are unavailable. Overall, the preponderance of evidence indicates that P924R 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 | 0.521092 | Disordered | 0.971858 | Binding | 0.293 | 0.846 | 0.250 | -6.024 | Likely Benign | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.420 | Likely Benign | -6.20 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.1314 | 0.2083 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2834A>C | H945P 2D AIThe SynGAP1 missense variant H945P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of benign predictions and the lack of pathogenic 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 | 0.982235 | Disordered | 0.849210 | Binding | 0.386 | 0.923 | 0.750 | -1.962 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.420 | Likely Benign | -0.34 | Neutral | 0.012 | Benign | 0.047 | Benign | 5.04 | Benign | 0.05 | Affected | 0.2730 | 0.3907 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3562G>C | D1188H 2D AIThe SynGAP1 D1188H 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, ESM1b, and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) indicate a pathogenic effect. 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. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -6.827 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.420 | Likely Benign | -3.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 5.41 | Benign | 0.00 | Affected | 0.0892 | 0.5242 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.3806T>G | V1269G 2D AIThe SynGAP1 missense variant V1269G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus is pathogenic; Foldetta results are unavailable. Based on the collective 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. | Coiled-coil | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -9.927 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.420 | Likely Benign | -5.91 | Deleterious | 0.995 | Probably Damaging | 0.999 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 0.2180 | 0.2557 | -1 | -3 | -4.6 | -42.08 | |||||||||||||||||||||||||||||||||||||||
| c.943A>T | N315Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315Y 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The 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 uncertain. Overall, the balance of evidence slightly favors a pathogenic interpretation, with six pathogenic‑predicted tools versus five benign‑predicted tools, and the high‑accuracy consensus leaning pathogenic. 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 | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -8.303 | Likely Pathogenic | 0.339 | Likely Benign | Likely Benign | -1.03 | Ambiguous | 0.5 | -0.85 | Ambiguous | -0.94 | Ambiguous | -0.10 | Likely Benign | 0.420 | Likely Benign | -3.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.93 | Pathogenic | 1.00 | Tolerated | 0.0613 | 0.6732 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1028T>G | V343G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—classify the variant as pathogenic. AlphaMissense‑Optimized is uncertain, providing no definitive direction. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Thus, the preponderance of evidence indicates that V343G 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. | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -11.332 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 2.49 | Destabilizing | 0.1 | 4.40 | Destabilizing | 3.45 | Destabilizing | 1.68 | Destabilizing | 0.421 | Likely Benign | -5.84 | Deleterious | 0.898 | Possibly Damaging | 0.996 | Probably Damaging | 1.60 | Pathogenic | 0.00 | Affected | 0.1982 | 0.3341 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1622C>G | A541G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A541G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438865‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default, and ESM1b) 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 inconclusive, and Foldetta is also inconclusive. Overall, the balance of evidence leans toward 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. | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | Uncertain | 1 | 6-33438865-C-G | 2 | 1.24e-6 | -7.233 | In-Between | 0.341 | Ambiguous | Likely Benign | 0.67 | Ambiguous | 0.0 | 0.94 | Ambiguous | 0.81 | Ambiguous | 0.76 | Ambiguous | 0.421 | Likely Benign | -1.48 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.31 | Pathogenic | 0.57 | Tolerated | 3.37 | 35 | 0.1787 | 0.2428 | 1 | 0 | -2.2 | -14.03 | 170.1 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Pathogenic | Ala541 is located on the outer surface of an α-helix (res. Ala533-Val560). The methyl group of Ala541 is on the surface and does not form any interactions. Glycine, known as an “α-helix breaker,” weakens the integrity of the helix. Indeed, in the variant simulations, the hydrogen bond formation between Gly541 and the backbone carbonyl of Ala537 is disrupted. | ||||||||||||||
| c.1912A>C | K638Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K638Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the 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 | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -9.561 | Likely Pathogenic | 0.556 | Ambiguous | Likely Benign | 0.45 | Likely Benign | 0.0 | 0.37 | Likely Benign | 0.41 | Likely Benign | 0.22 | Likely Benign | 0.421 | Likely Benign | -3.60 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.42 | Benign | 0.12 | Tolerated | 0.3623 | 0.0920 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| c.2831G>A | G944D 2D AIThe SynGAP1 missense variant G944D is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools largely support a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the majority‑vote SGM‑Consensus also indicates a likely benign outcome. Only SIFT predicts a pathogenic effect, and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign classification. Foldetta stability analysis is not available for this residue. Overall, the preponderance of evidence points to a benign impact, and this assessment does not conflict with the absence of a ClinVar claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -7.684 | In-Between | 0.296 | Likely Benign | Likely Benign | 0.421 | Likely Benign | -1.42 | Neutral | 0.224 | Benign | 0.131 | Benign | 3.70 | Benign | 0.00 | Affected | 0.1833 | 0.2826 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3478A>T | N1160Y 2D AIThe SynGAP1 missense variant N1160Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” No Foldetta stability prediction is available. Overall, the preponderance of evidence indicates that 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 | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -4.074 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.421 | Likely Benign | -4.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.01 | Affected | 0.0591 | 0.5681 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||||||||||||
| c.3584T>C | V1195A 2D AIThe SynGAP1 missense variant V1195A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default both predict a pathogenic outcome. 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 pathogenic, whereas the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the balance of evidence leans toward a benign impact, 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 Benign | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -4.291 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.421 | Likely Benign | -0.84 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.60 | Benign | 0.44 | Tolerated | 0.2602 | 0.1854 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||||||
| c.629A>T | H210L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210L missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: benign predictions come from REVEL, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta provide uncertain results. 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 (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -14.516 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.71 | Ambiguous | 0.1 | 1.35 | Ambiguous | 0.32 | Likely Benign | 0.49 | Likely Benign | 0.421 | Likely Benign | -9.41 | Deleterious | 0.895 | Possibly Damaging | 0.614 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.0617 | 0.4452 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.709G>T | A237S 2D AIThe SynGAP1 missense variant A237S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS and ESM1b, 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, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -7.696 | In-Between | 0.112 | Likely Benign | Likely Benign | 0.48 | Likely Benign | 0.6 | 0.34 | Likely Benign | 0.41 | Likely Benign | 0.61 | Ambiguous | 0.421 | Likely Benign | -1.41 | Neutral | 0.259 | Benign | 0.048 | Benign | 5.82 | Benign | 0.31 | Tolerated | 0.2209 | 0.4357 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1139G>C | G380A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G380A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FoldX predicts a pathogenic outcome, while Rosetta and Foldetta are benign or uncertain, respectively. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta as uncertain. Overall, the overwhelming majority of evidence points to a benign effect, with no conflict with ClinVar status (which has no entry for this variant). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -6.433 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 3.11 | Destabilizing | 1.0 | -0.15 | Likely Benign | 1.48 | Ambiguous | -0.06 | Likely Benign | 0.422 | Likely Benign | -0.53 | Neutral | 0.056 | Benign | 0.010 | Benign | 2.56 | Benign | 0.17 | Tolerated | 0.3915 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| 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.2086C>T | L696F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L696F has no ClinVar entry and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, and FATHMM. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 benign. 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 | 0.200174 | Structured | 0.390093 | Uncertain | 0.962 | 0.267 | 0.000 | -9.651 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.14 | Likely Benign | 0.1 | 0.74 | Ambiguous | 0.44 | Likely Benign | 0.55 | Ambiguous | 0.422 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.05 | Benign | 0.00 | Affected | 0.0667 | 0.2008 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2771C>T | P924L 2D AIThe SynGAP1 missense variant P924L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that P924L is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.521092 | Disordered | 0.971858 | Binding | 0.293 | 0.846 | 0.250 | -6.361 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.422 | Likely Benign | -6.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.1771 | 0.4941 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3388A>G | K1130E 2D AIThe SynGAP1 missense variant K1130E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, while AlphaMissense‑Optimized remains Uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of tools and the SGM consensus support a benign impact, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. 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 | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -4.998 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.422 | Likely Benign | -1.23 | Neutral | 0.649 | Possibly Damaging | 0.266 | Benign | 5.45 | Benign | 0.00 | Affected | 0.4251 | 0.1876 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3686A>C | Q1229P 2D AIThe SynGAP1 missense variant Q1229P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is “Likely Pathogenic.” No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence points to a pathogenic 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 Pathogenic | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | Uncertain | 1 | -10.397 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.422 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.75 | Pathogenic | 0.12 | Tolerated | 3.77 | 5 | 0.2197 | 0.4107 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||
| c.1412C>T | S471F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining tools—AlphaMissense‑Default, FoldX, Rosetta, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Taken together, the majority of evidence points toward a pathogenic impact for S471F, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -10.777 | Likely Pathogenic | 0.492 | Ambiguous | Likely Benign | -0.54 | Ambiguous | 0.1 | -1.51 | Ambiguous | -1.03 | Ambiguous | 0.12 | Likely Benign | 0.423 | Likely Benign | -4.75 | Deleterious | 0.942 | Possibly Damaging | 0.487 | Possibly Damaging | -1.26 | Pathogenic | 0.02 | Affected | 0.0553 | 0.4691 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| 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.1989T>A | F663L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L 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 (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM Consensus, premPS, and Rosetta) indicate a pathogenic impact. FoldX‑MD and Rosetta‑based stability calculations are inconclusive, yielding an uncertain Foldetta result. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence from consensus and high‑accuracy tools points to a pathogenic effect for F663L. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -11.996 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.1 | 2.01 | Destabilizing | 1.46 | Ambiguous | 1.51 | Destabilizing | 0.423 | Likely Benign | -5.99 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.1973 | 0.2936 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1989T>G | F663L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L 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 (PolyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and the SGM Consensus) indicate a pathogenic impact. FoldX‑MD and Rosetta give conflicting stability results, with FoldX uncertain and Rosetta pathogenic; Foldetta, which integrates both, is also uncertain. 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 F663L. 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 | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -11.996 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.91 | Ambiguous | 0.1 | 2.01 | Destabilizing | 1.46 | Ambiguous | 1.51 | Destabilizing | 0.423 | Likely Benign | -5.99 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.1973 | 0.2936 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.3404A>T | K1135M 2D AIThe SynGAP1 K1135M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. 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 Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the balance of evidence leans toward a benign interpretation, and 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. | Likely Benign | 0.887230 | Disordered | 0.790969 | Binding | 0.303 | 0.889 | 0.875 | -5.953 | Likely Benign | 0.931 | Likely Pathogenic | Ambiguous | 0.423 | Likely Benign | -1.65 | Neutral | 0.938 | Possibly Damaging | 0.819 | Possibly Damaging | 5.42 | Benign | 0.02 | Affected | 0.1669 | 0.4164 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3440C>T | T1147I 2D  AIThe SynGAP1 missense variant T1147I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.552 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.423 | Likely Benign | -2.03 | Neutral | 0.259 | Benign | 0.059 | Benign | 5.42 | Benign | 0.01 | Affected | 0.1029 | 0.4968 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3565G>A | E1189K 2D AIThe SynGAP1 missense variant E1189K is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. 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 results are unavailable. Overall, the balance of evidence—five benign predictions versus three pathogenic ones, a consensus benign rating, and no conflicting ClinVar annotation—suggests that E1189K is most likely benign. 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 | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -5.565 | Likely Benign | 0.947 | Likely Pathogenic | Ambiguous | 0.423 | Likely Benign | -1.64 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.37 | Benign | 0.08 | Tolerated | 0.1597 | 0.4046 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3674C>T | S1225F 2D AIThe SynGAP1 missense variant S1225F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1225F, 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 | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -7.938 | In-Between | 0.328 | Likely Benign | Likely Benign | 0.423 | Likely Benign | -2.34 | Neutral | 0.927 | Possibly Damaging | 0.690 | Possibly Damaging | 5.37 | Benign | 0.06 | Tolerated | 0.0505 | 0.4979 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||
| c.3818T>A | L1273Q 2D AIThe SynGAP1 missense variant L1273Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic and the SGM‑Consensus is labeled Likely Pathogenic; Foldetta results are unavailable. Based on the preponderance of evidence, 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 | 0.599170 | Disordered | 0.773625 | Binding | 0.747 | 0.677 | 0.500 | -6.813 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.423 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.950 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.1139 | 0.1119 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.1988T>A | F663Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663Y 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. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. 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 tools and the SGM‑Consensus lean toward pathogenicity, while a minority suggest benign impact. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.056825 | Structured | 0.093963 | Uncertain | 0.944 | 0.355 | 0.000 | -12.749 | Likely Pathogenic | 0.853 | Likely Pathogenic | Ambiguous | 0.37 | Likely Benign | 0.1 | 0.19 | Likely Benign | 0.28 | Likely Benign | 1.03 | Destabilizing | 0.424 | Likely Benign | -2.99 | Deleterious | 0.984 | Probably Damaging | 0.913 | Probably Damaging | 3.11 | Benign | 0.05 | Affected | 0.1243 | 0.1584 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.2159A>C | D720A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720A 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 SIFT, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome, whereas Foldetta (combining FoldX‑MD and Rosetta) predicts a benign impact, and AlphaMissense‑Optimized remains uncertain. Overall, the predictions are split, with a slight tilt toward pathogenicity from the consensus and high‑accuracy methods. Thus, the variant is most likely pathogenic based on the available predictions, and this 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 | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -10.999 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | -0.14 | Likely Benign | 0.0 | -0.35 | Likely Benign | -0.25 | Likely Benign | 0.40 | Likely Benign | 0.424 | Likely Benign | -6.20 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.16 | Pathogenic | 0.11 | Tolerated | 0.3726 | 0.5551 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.2776T>C | S926P 2D AIThe SynGAP1 missense variant S926P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), yielding a Likely Pathogenic classification. AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for S926P. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -3.873 | Likely Benign | 0.916 | Likely Pathogenic | Ambiguous | 0.424 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.1738 | 0.5058 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3656A>C | Y1219S 2D AIThe SynGAP1 missense variant Y1219S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—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 predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective evidence, the variant is most likely pathogenic, 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 Pathogenic | Coiled-coil | 0.613573 | Disordered | 0.474748 | Uncertain | 0.855 | 0.557 | 0.375 | -11.227 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.424 | Likely Benign | -6.05 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.18 | Pathogenic | 0.00 | Affected | 0.5047 | 0.1403 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||
| c.3797T>C | L1266P 2D AIThe SynGAP1 missense variant L1266P is reported in gnomAD (6‑33447845‑T‑C) but has no ClinVar entry. Prediction tools cluster into two groups: benign predictions are made only by REVEL, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized returns a pathogenic score, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic.” The Foldetta stability analysis is unavailable for this variant. Overall, the consensus of both general and high‑accuracy predictors points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.433034 | Structured | 0.802655 | Binding | 0.868 | 0.602 | 0.000 | 6-33447845-T-C | -16.566 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.424 | Likely Benign | -5.83 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3150 | 0.2283 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| 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.2162T>A | I721N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, 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 from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | -14.905 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.0 | 3.21 | Destabilizing | 3.02 | Destabilizing | 2.10 | Destabilizing | 0.425 | Likely Benign | -6.30 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.19 | Pathogenic | 0.00 | Affected | 0.0737 | 0.0340 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.3413C>G | S1138C 2D AIThe SynGAP1 missense variant S1138C is catalogued in gnomAD (ID 6‑33444448‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for S1138C. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | 6-33444448-C-G | 1 | 6.20e-7 | -7.850 | In-Between | 0.117 | Likely Benign | Likely Benign | 0.425 | Likely Benign | -2.48 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 5.40 | Benign | 0.04 | Affected | 4.32 | 4 | 0.1472 | 0.6396 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.3439A>C | T1147P 2D  AIThe SynGAP1 missense variant T1147P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. 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 | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -2.849 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.425 | Likely Benign | -2.17 | Neutral | 0.000 | Benign | 0.002 | Benign | 5.41 | Benign | 0.02 | Affected | 0.1925 | 0.4490 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.823C>A | P275T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P275T is reported in gnomAD (ID 6‑33437728‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain and therefore not considered evidence. No other tools provide conclusive results. Overall, the majority of predictions, including the SGM‑Consensus, indicate a pathogenic effect, and this assessment does not contradict any ClinVar classification because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | 6-33437728-C-A | 3 | 1.86e-6 | -8.708 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 0.3 | 1.15 | Ambiguous | 1.80 | Ambiguous | 0.69 | Ambiguous | 0.425 | Likely Benign | -5.38 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0.1808 | 0.4000 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||
| c.988G>C | D330H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign predictions are limited to REVEL; pathogenic predictions include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, FoldX, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic impact for D330H. This conclusion is not contradicted by any ClinVar annotation, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -13.926 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 2.29 | Destabilizing | 0.6 | 1.32 | Ambiguous | 1.81 | Ambiguous | 0.61 | Ambiguous | 0.425 | Likely Benign | -4.67 | Deleterious | 0.998 | Probably Damaging | 0.961 | Probably Damaging | 0.96 | Pathogenic | 0.01 | Affected | 0.1608 | 0.4843 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1406C>T | A469V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A469V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect comprise FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and Foldetta; premPS and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts pathogenic. With seven tools supporting pathogenicity versus four supporting benignity, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.278302 | Structured | 0.343926 | Uncertain | 0.910 | 0.276 | 0.000 | -8.858 | Likely Pathogenic | 0.459 | Ambiguous | Likely Benign | 2.30 | Destabilizing | 0.4 | 2.66 | Destabilizing | 2.48 | Destabilizing | -0.77 | Ambiguous | 0.426 | Likely Benign | 0.26 | Neutral | 0.997 | Probably Damaging | 0.976 | Probably Damaging | -1.20 | Pathogenic | 0.60 | Tolerated | 0.0827 | 0.5421 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.2534A>T | D845V 2D AIThe SynGAP1 D845V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL classifies it as benign, whereas the remaining 11 predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a harmful outcome: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic; Foldetta results are not available. Taken together, the overwhelming majority of evidence points to a pathogenic effect. 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 | 0.553315 | Disordered | 0.599971 | Binding | 0.297 | 0.827 | 0.500 | -8.914 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.426 | Likely Benign | -6.15 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.00 | Affected | 0.0871 | 0.7088 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2830G>T | G944C 2D AIThe SynGAP1 missense variant G944C is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6‑33443382‑G‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote of the four contributing tools) also indicates Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | 6-33443382-G-T | 1 | 6.20e-7 | -9.121 | Likely Pathogenic | 0.093 | Likely Benign | Likely Benign | 0.426 | Likely Benign | -1.79 | Neutral | 0.975 | Probably Damaging | 0.848 | Possibly Damaging | 3.70 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1399 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.3503T>C | I1168T 2D AIThe SynGAP1 missense variant I1168T 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, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” AlphaMissense‑Optimized is uncertain, and no Foldetta stability result is available. Overall, the high‑accuracy consensus (SGM‑Consensus) points to a benign outcome, whereas AlphaMissense‑Optimized remains inconclusive. Thus, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -2.970 | Likely Benign | 0.943 | Likely Pathogenic | Ambiguous | 0.426 | Likely Benign | -1.29 | Neutral | 0.992 | Probably Damaging | 0.933 | Probably Damaging | 5.54 | Benign | 0.04 | Affected | 0.1173 | 0.1647 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3515A>T | H1172L 2D AIThe SynGAP1 missense variant H1172L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for H1172L, 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 Benign | Coiled-coil | 0.626927 | Disordered | 0.673805 | Binding | 0.465 | 0.758 | 0.625 | -0.545 | Likely Benign | 0.446 | Ambiguous | Likely Benign | 0.426 | Likely Benign | -2.30 | Neutral | 0.451 | Benign | 0.265 | Benign | 5.47 | Benign | 0.01 | Affected | 0.0815 | 0.5285 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||
| c.3776T>G | I1259S 2D  AIThe SynGAP1 missense variant I1259S 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 the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled “Likely Pathogenic.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence indicates that 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 | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -12.269 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.426 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | 0.3004 | 0.1110 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.4003G>T | G1335C 2D AIThe SynGAP1 missense variant G1335C is listed in gnomAD (variant ID 6-33451877‑G‑T) but has no ClinVar entry. Functional prediction tools split into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, 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 pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also indicates Likely Pathogenic. Foldetta results are not available for this variant. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | 6-33451877-G-T | 1 | 7.91e-7 | -6.878 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.426 | Likely Benign | -5.51 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.01 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1376 | 0.4513 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||
| c.1109G>T | G370V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score of Likely Benign) and pathogenic (FoldX, Rosetta, Foldetta, and FATHMM). High‑accuracy assessments further refine this picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic outcome. Overall, the majority of evidence points toward a benign impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -5.328 | Likely Benign | 0.094 | Likely Benign | Likely Benign | 4.98 | Destabilizing | 3.8 | 5.61 | Destabilizing | 5.30 | Destabilizing | -0.43 | Likely Benign | 0.427 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.32 | Pathogenic | 0.29 | Tolerated | 0.1306 | 0.4198 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1213C>T | R405C 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R405C is listed in ClinVar with an uncertain significance (ClinVar ID 1185858.0) and is present in gnomAD (ID 6‑33438118‑C‑T). Prediction tools that indicate a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually return uncertain results. Overall, the balance of evidence favors a pathogenic interpretation, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Conflicting | 2 | 6-33438118-C-T | 6 | 3.72e-6 | -9.206 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.72 | Ambiguous | 0.1 | 1.51 | Ambiguous | 1.12 | Ambiguous | 1.21 | Destabilizing | 0.427 | Likely Benign | -7.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.61 | Benign | 0.02 | Affected | 3.38 | 28 | 0.3227 | 0.3964 | -4 | -3 | 7.0 | -53.05 | 221.3 | 82.6 | -0.1 | 0.0 | -0.2 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Ala399-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the thiol-containing side chain of Cys405 is neutral and smaller compared to the arginine side chain. The lack of Arg405-Phe358 stacking affects the loop structure, causing it to assume a β strand form—an effect that could be exacerbated during protein folding. Moreover, the inability of Cys405 to form a salt bridge with Glu446 could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | ||||||||||||
| c.1729G>A | A577T 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant A577T is listed in ClinVar as benign (ClinVar ID 2195056.0) and is present in gnomAD (ID 6‑33440781‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, 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, reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other high‑confidence stability predictions are available. Overall, the consensus of the available predictions indicates that the variant is most likely benign, which aligns with its ClinVar classification and does not contradict the reported status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | Benign | 1 | 6-33440781-G-A | 6 | 3.72e-6 | -5.311 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.86 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.70 | Ambiguous | 0.54 | Ambiguous | 0.427 | Likely Benign | -1.47 | Neutral | 0.999 | Probably Damaging | 0.987 | Probably Damaging | -1.31 | Pathogenic | 0.47 | Tolerated | 3.37 | 34 | 0.1657 | 0.5875 | 1 | 0 | -2.5 | 30.03 | 191.9 | -43.4 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | Ala577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. In the variant simulations, the hydroxyl group of the Thr577 side chain hydrogen bonds with the backbone atoms of Arg573 and Lys574 within the same helix, which has the potential to weaken the stability of the secondary structure element. Regardless, the residue swap seems to be well tolerated based on the variant simulations. | |||||||||||||
| c.2159A>G | D720G 2D AISynGAP1 missense variant D720G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools remain inconclusive: 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 (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -11.130 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.4 | 0.53 | Ambiguous | 0.49 | Likely Benign | 0.46 | Likely Benign | 0.427 | Likely Benign | -5.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.15 | Pathogenic | 0.01 | Affected | 0.4027 | 0.5011 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.3566A>C | E1189A 2D AIThe SynGAP1 missense variant E1189A is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑vs‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are evenly divided between benign and pathogenic, with no high‑confidence consensus. Thus, the variant is most likely of uncertain significance; there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -4.989 | Likely Benign | 0.860 | Likely Pathogenic | Ambiguous | 0.427 | Likely Benign | -3.06 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.34 | Benign | 0.09 | Tolerated | 0.2827 | 0.4105 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.628C>T | H210Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210Y 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. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus score is “Likely Pathogenic.” 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 impact, and this conclusion does not contradict any ClinVar classification because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.828 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.8 | 0.38 | Likely Benign | 0.33 | Likely Benign | 0.39 | Likely Benign | 0.427 | Likely Benign | -5.12 | Deleterious | 0.963 | Probably Damaging | 0.628 | Possibly Damaging | 3.07 | Benign | 0.00 | Affected | 0.0497 | 0.3662 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||
| c.1118G>T | G373V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G373V is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33438023‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are FoldX, Foldetta, and SIFT, while Rosetta is inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as pathogenic. Overall, the majority of predictions support a benign impact, and this consensus does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | Uncertain | 1 | 6-33438023-G-T | 6 | 5.03e-6 | -6.062 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 5.32 | Destabilizing | 3.2 | 0.82 | Ambiguous | 3.07 | Destabilizing | 0.09 | Likely Benign | 0.428 | Likely Benign | -0.98 | Neutral | 0.007 | Benign | 0.001 | Benign | 3.90 | Benign | 0.00 | Affected | 3.53 | 16 | 0.1424 | 0.4004 | -1 | -3 | 4.6 | 42.08 | 207.6 | -68.1 | 1.9 | 1.1 | -0.6 | 0.1 | Uncertain | Gly373 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like valine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Val373 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on the Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||
| c.1253A>T | K418I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K418I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM. In contrast, the majority of tools predict a pathogenic outcome: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K418I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.360134 | Uncertain | 0.948 | 0.263 | 0.000 | -14.895 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.51 | Ambiguous | 0.0 | 0.64 | Ambiguous | 0.58 | Ambiguous | 0.27 | Likely Benign | 0.428 | Likely Benign | -7.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | 0.1297 | 0.2432 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.1595C>T | T532I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) reports a benign effect. Overall, the balance of evidence leans toward pathogenicity, 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 | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -9.031 | Likely Pathogenic | 0.591 | Likely Pathogenic | Likely Benign | -0.11 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.38 | Likely Benign | 0.22 | Likely Benign | 0.428 | Likely Benign | -3.31 | Deleterious | 0.633 | Possibly Damaging | 0.202 | Benign | -1.31 | Pathogenic | 0.03 | Affected | 0.0713 | 0.4983 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.2477A>T | D826V 2D AIThe SynGAP1 missense variant D826V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and 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 that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for D826V, and this conclusion does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -6.918 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.428 | Likely Benign | -4.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.48 | Pathogenic | 0.00 | Affected | 0.1017 | 0.8023 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.2849G>T | G950V 2D AIThe SynGAP1 missense variant G950V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that G950V is most likely benign, 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. | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -7.796 | In-Between | 0.093 | Likely Benign | Likely Benign | 0.428 | Likely Benign | -0.91 | Neutral | 0.411 | Benign | 0.239 | Benign | 2.26 | Pathogenic | 0.01 | Affected | 0.1392 | 0.3507 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.989A>T | D330V 2D 3DClick to see structure in 3D Viewer AISynGAP1 D330V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and premPS, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, and AlphaMissense‑Default. Uncertain predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are treated as unavailable. High‑accuracy assessments show that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized and Foldetta provide inconclusive results and are therefore not considered evidence. Overall, the preponderance of evidence points to a pathogenic effect for D330V, 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 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -13.176 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 2.06 | Destabilizing | 0.5 | 0.57 | Ambiguous | 1.32 | Ambiguous | 0.45 | Likely Benign | 0.428 | Likely Benign | -6.40 | Deleterious | 0.994 | Probably Damaging | 0.892 | Possibly Damaging | 0.89 | Pathogenic | 0.01 | Affected | 0.0862 | 0.4633 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1903A>C | N635H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Three tools (FoldX, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; and Foldetta predicts benign. No prediction or folding‑stability result is missing or inconclusive. Based on the available evidence, 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 | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -12.507 | Likely Pathogenic | 0.419 | Ambiguous | Likely Benign | 1.07 | Ambiguous | 0.2 | -0.10 | Likely Benign | 0.49 | Likely Benign | 0.91 | Ambiguous | 0.429 | Likely Benign | -4.78 | Deleterious | 0.993 | Probably Damaging | 0.879 | Possibly Damaging | 2.90 | Benign | 0.00 | Affected | 0.1184 | 0.3720 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||
| c.1990T>A | L664M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664M 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, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also uncertain due to a 2‑vs‑2 split; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of conventional tools predict a pathogenic impact, whereas the high‑accuracy methods do not provide a definitive verdict. Consequently, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -11.819 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.1 | 1.35 | Ambiguous | 0.92 | Ambiguous | 0.96 | Ambiguous | 0.429 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 2.92 | Benign | 0.01 | Affected | 0.0620 | 0.2541 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.3710A>G | Y1237C 2D AIThe SynGAP1 missense variant Y1237C is listed in gnomAD (variant ID 6‑33446702‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic effect. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized reports a pathogenic outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Pathogenic.” No Foldetta stability result is available, so it does not influence the overall assessment. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.653063 | Disordered | 0.563444 | Binding | 0.842 | 0.535 | 0.125 | 6-33446702-A-G | 1 | 6.20e-7 | -8.600 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.429 | Likely Benign | -7.15 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.43 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.3354 | 0.1549 | -2 | 0 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||
| c.1135T>C | S379P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, Rosetta, and Foldetta; FoldX is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of evidence—including the high‑accuracy benign predictions—suggests that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | -5.007 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 1.10 | Ambiguous | 0.8 | 2.92 | Destabilizing | 2.01 | Destabilizing | 0.17 | Likely Benign | 0.430 | Likely Benign | -0.41 | Neutral | 0.808 | Possibly Damaging | 0.212 | Benign | 3.83 | Benign | 0.10 | Tolerated | 0.3035 | 0.6594 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1159G>T | G387C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G387C is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438064‑G‑T). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, 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 (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of high‑confidence tools lean toward a benign interpretation, and this does not contradict the ClinVar status, which has no pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | 6-33438064-G-T | 1 | 6.21e-7 | -7.609 | In-Between | 0.146 | Likely Benign | Likely Benign | 2.88 | Destabilizing | 0.6 | 2.34 | Destabilizing | 2.61 | Destabilizing | -0.03 | Likely Benign | 0.430 | Likely Benign | -0.58 | Neutral | 0.859 | Possibly Damaging | 0.346 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 3 | 0.1589 | 0.4240 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||
| c.1183G>A | G395R 2D AIThe SynGAP1 missense variant G395R has no ClinVar record and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, yield uncertain results. 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 remains uncertain. Overall, the balance of evidence favors a benign effect, 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. | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -9.851 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.26 | Ambiguous | 2.1 | -0.25 | Likely Benign | 0.51 | Ambiguous | 0.50 | Likely Benign | 0.430 | Likely Benign | -2.01 | Neutral | 0.037 | Benign | 0.027 | Benign | 4.23 | Benign | 0.02 | Affected | 0.0953 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1183G>C | G395R 2D AIThe SynGAP1 missense variant G395R has no ClinVar record and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from SIFT, ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Foldetta, yield uncertain results. 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 remains uncertain. Overall, the balance of evidence favors a benign effect, 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. | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -9.851 | Likely Pathogenic | 0.768 | Likely Pathogenic | Likely Benign | 1.26 | Ambiguous | 2.1 | -0.25 | Likely Benign | 0.51 | Ambiguous | 0.50 | Likely Benign | 0.430 | Likely Benign | -2.01 | Neutral | 0.037 | Benign | 0.027 | Benign | 4.23 | Benign | 0.02 | Affected | 0.0953 | 0.4313 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| 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.2528T>G | M843R 2D  AIThe SynGAP1 missense variant M843R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that M843R is most likely pathogenic, 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 Pathogenic | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -12.044 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.430 | Likely Benign | -3.78 | Deleterious | 0.968 | Probably Damaging | 0.978 | Probably Damaging | 2.59 | Benign | 0.00 | Affected | 0.1819 | 0.0922 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.824C>T | P275L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275L is not reported in ClinVar and is absent from gnomAD. In silico predictions cluster into two groups: benign predictions come from REVEL, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant 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. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of tools predict pathogenicity, and the high‑accuracy consensus supports a likely pathogenic classification. This prediction does not contradict any ClinVar status, as the variant is currently unreported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | -9.785 | Likely Pathogenic | 0.304 | Likely Benign | Likely Benign | 1.63 | Ambiguous | 0.2 | 1.22 | Ambiguous | 1.43 | Ambiguous | 0.29 | Likely Benign | 0.430 | Likely Benign | -6.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.83 | Pathogenic | 0.00 | Affected | 0.2139 | 0.5056 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.845G>T | C282F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282F is not listed in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by REVEL and premPS, whereas the remaining 13 tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic outcome. Taken together, the overwhelming majority of evidence points to a pathogenic impact for C282F. This conclusion is consistent with the absence of a ClinVar entry, which does not contradict the prediction. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -13.288 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 6.22 | Destabilizing | 1.4 | 2.38 | Destabilizing | 4.30 | Destabilizing | 0.42 | Likely Benign | 0.430 | Likely Benign | -10.11 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 0.1267 | 0.3607 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.875C>T | A292V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, 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. Based on the overwhelming agreement among these predictions, 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 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -11.170 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.04 | Destabilizing | 0.5 | 4.60 | Destabilizing | 3.32 | Destabilizing | 0.85 | Ambiguous | 0.430 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1272 | 0.6253 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.961C>G | R321G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, AlphaMissense‑Default, AlphaMissense‑Optimized, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, while the high‑accuracy subset is mixed, with one benign, one pathogenic, and one uncertain result. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -10.554 | Likely Pathogenic | 0.293 | Likely Benign | Likely Benign | 0.90 | Ambiguous | 0.1 | 0.28 | Likely Benign | 0.59 | Ambiguous | 0.49 | Likely Benign | 0.430 | Likely Benign | -3.70 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.92 | Pathogenic | 0.04 | Affected | 0.3224 | 0.2898 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| 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.3605T>G | I1202S 2D AIThe SynGAP1 missense variant I1202S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. 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 and the SGM‑Consensus as Likely Pathogenic; Foldetta results are not available. Based on the collective evidence, the variant is most likely pathogenic, 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 Pathogenic | Coiled-coil | 0.529623 | Disordered | 0.510422 | Binding | 0.874 | 0.593 | 0.250 | -11.877 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.431 | Likely Benign | -4.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.3021 | 0.0640 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3818T>G | L1273R 2D AIThe SynGAP1 missense variant L1273R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus outcome, the variant is most likely pathogenic; this assessment is not contradicted by any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.773625 | Binding | 0.747 | 0.677 | 0.500 | -6.252 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.431 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.13 | Pathogenic | 0.00 | Affected | 0.1369 | 0.0761 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.629A>G | H210R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H210R missense variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and FoldX, whereas a majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). The high‑accuracy AlphaMissense‑Optimized result is pathogenic; the SGM Consensus, based on the same set of predictors, is also pathogenic; Foldetta’s stability assessment is uncertain and therefore not considered evidence. Overall, the balance of evidence points to a pathogenic effect for H210R. This prediction does not contradict the ClinVar “Uncertain” classification, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | Uncertain | 1 | -14.254 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.4 | 3.05 | Destabilizing | 1.73 | Ambiguous | 1.12 | Destabilizing | 0.431 | Likely Benign | -6.74 | Deleterious | 0.808 | Possibly Damaging | 0.452 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1427 | 0.1982 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||
| c.1244A>G | E415G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for E415G. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -12.244 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 1.16 | Ambiguous | 0.2 | 0.88 | Ambiguous | 1.02 | Ambiguous | 0.65 | Ambiguous | 0.432 | Likely Benign | -6.45 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.20 | Benign | 0.01 | Affected | 0.2518 | 0.3158 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1393C>T | L465F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L465F is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and Rosetta, whereas the majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Two tools (Foldetta and premPS) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus also pathogenic, and Foldetta remains uncertain. Overall, the consensus of high‑confidence predictors points to a pathogenic effect for L465F. This conclusion is not contradicted by ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.346032 | Structured | 0.319240 | Uncertain | 0.956 | 0.202 | 0.000 | -12.626 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 3.11 | Destabilizing | 0.7 | 0.05 | Likely Benign | 1.58 | Ambiguous | 0.52 | Ambiguous | 0.432 | Likely Benign | -3.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.0771 | 0.2759 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1605T>A | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. This conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.432 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1605T>G | S535R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls come from polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta is also inconclusive. Overall, the balance of evidence, particularly the SGM Consensus, points to a pathogenic effect. This conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -9.363 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.0 | -0.97 | Ambiguous | -0.67 | Ambiguous | 0.64 | Ambiguous | 0.432 | Likely Benign | -1.99 | Neutral | 0.830 | Possibly Damaging | 0.274 | Benign | -1.23 | Pathogenic | 0.19 | Tolerated | 3.37 | 35 | 0.1086 | 0.3743 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||
| c.1903A>G | N635D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and FATHMM. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Predictions that are inconclusive are Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy methods give an uncertain result for AlphaMissense‑Optimized, a Likely Pathogenic verdict from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain outcome from Foldetta. Overall, the majority of computational evidence points to a pathogenic effect, 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 | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -14.453 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 0.47 | Likely Benign | 0.1 | 0.73 | Ambiguous | 0.60 | Ambiguous | 1.26 | Destabilizing | 0.432 | Likely Benign | -4.71 | Deleterious | 0.955 | Possibly Damaging | 0.628 | Possibly Damaging | 2.92 | Benign | 0.01 | Affected | 0.1725 | 0.1937 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.2005A>C | N669H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669H has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are uncertain and 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 majority of evidence points toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.364 | Likely Pathogenic | 0.421 | Ambiguous | Likely Benign | 1.26 | Ambiguous | 0.2 | 1.69 | Ambiguous | 1.48 | Ambiguous | 0.80 | Ambiguous | 0.432 | Likely Benign | -4.49 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | 0.1732 | 0.4839 | 2 | 1 | 0.3 | 23.04 | ||||||||||||||||||||||||||||||
| c.2132T>G | L711R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L711R 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 and FATHMM; all other evaluated algorithms (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 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 or stability results are missing or inconclusive. Based on the overwhelming majority of computational 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 | 0.308712 | Structured | 0.377436 | Uncertain | 0.950 | 0.364 | 0.000 | -14.009 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.71 | Destabilizing | 0.0 | 3.98 | Destabilizing | 3.85 | Destabilizing | 2.13 | Destabilizing | 0.432 | Likely Benign | -5.71 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.35 | Benign | 0.00 | Affected | 0.1345 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.3166G>T | G1056C 2D AIThe SynGAP1 missense variant G1056C is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. 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 results are unavailable. Overall, the balance of evidence leans toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -9.974 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.432 | Likely Benign | -0.70 | Neutral | 0.994 | Probably Damaging | 0.777 | Possibly Damaging | 1.83 | Pathogenic | 0.06 | Tolerated | 0.1414 | 0.4439 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||||
| c.3386T>C | L1129P 2D AIThe SynGAP1 missense variant L1129P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | Uncertain | 2 | -2.991 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.432 | Likely Benign | 0.27 | Neutral | 0.971 | Probably Damaging | 0.773 | Possibly Damaging | 5.44 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3017 | 0.2231 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||
| c.1112G>T | S371I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371I 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 and Rosetta, 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, PROVEAN) also yields benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign effect. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -6.888 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.4 | -0.50 | Ambiguous | 0.00 | Likely Benign | -0.11 | Likely Benign | 0.433 | Likely Benign | -1.06 | Neutral | 0.028 | Benign | 0.016 | Benign | 4.62 | Benign | 0.07 | Tolerated | 0.1423 | 0.5924 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.1296T>G | C432W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments reinforce this: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus indicates a likely pathogenic status, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result, providing no counter‑evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.936 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.4 | 0.72 | Ambiguous | 0.95 | Ambiguous | 0.58 | Ambiguous | 0.433 | Likely Benign | -10.50 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.43 | Benign | 0.00 | Affected | 0.1217 | 0.3246 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| 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.1672C>A | H558N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H558N missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, ESM1b, and FATHMM. Uncertain results come from premPS and Rosetta. 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 evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.011039 | Uncertain | 0.897 | 0.200 | 0.000 | -9.523 | Likely Pathogenic | 0.257 | Likely Benign | Likely Benign | -0.22 | Likely Benign | 0.1 | 0.82 | Ambiguous | 0.30 | Likely Benign | 0.98 | Ambiguous | 0.433 | Likely Benign | -4.58 | Deleterious | 0.388 | Benign | 0.327 | Benign | -1.25 | Pathogenic | 0.14 | Tolerated | 0.1466 | 0.1281 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.3473T>G | V1158G 2D AIThe SynGAP1 missense variant V1158G 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 ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic outcome. High‑accuracy assessments reinforce this pattern: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that V1158G is most likely pathogenic, 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. | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -3.058 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.433 | Likely Benign | -4.62 | Deleterious | 0.997 | Probably Damaging | 0.999 | Probably Damaging | 2.30 | Pathogenic | 0.00 | Affected | 0.1870 | 0.3289 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.1295G>T | C432F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432F is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -12.862 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | -0.44 | Likely Benign | 0.2 | -0.34 | Likely Benign | -0.39 | Likely Benign | 0.57 | Ambiguous | 0.434 | Likely Benign | -10.50 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.46 | Benign | 0.01 | Affected | 0.1090 | 0.3956 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| 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.3532T>G | Y1178D 2D  AIThe SynGAP1 missense variant Y1178D 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, PROVEAN, SIFT, ESM1b, and FATHMM, while those 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, reports the variant as Likely Benign. AlphaMissense‑Optimized yields an Uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the balance of evidence from high‑accuracy tools and consensus predictions leans toward a benign classification. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -1.250 | Likely Benign | 0.801 | Likely Pathogenic | Ambiguous | 0.434 | Likely Benign | -1.33 | Neutral | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 5.55 | Benign | 0.07 | Tolerated | 0.4562 | 0.0173 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.812C>G | A271G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or unavailable stability results and are not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as unavailable. 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 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 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | -9.508 | Likely Pathogenic | 0.183 | Likely Benign | Likely Benign | 1.73 | Ambiguous | 0.1 | 1.43 | Ambiguous | 1.58 | Ambiguous | 1.31 | Destabilizing | 0.434 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.89 | Pathogenic | 0.01 | Affected | 0.1869 | 0.2388 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1244A>C | E415A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E415A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are given by FoldX and premPS. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy predictions support this view. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.743 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.2 | 0.05 | Likely Benign | 0.33 | Likely Benign | 0.53 | Ambiguous | 0.435 | Likely Benign | -5.56 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.19 | Benign | 0.03 | Affected | 0.2909 | 0.3432 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| 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.1456G>A | E486K 2D 3DClick to see structure in 3D Viewer AISynGAP1 E486K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Because the predictions are split evenly and the high‑accuracy tools are contradictory, the variant’s impact remains uncertain; thus, the variant is most likely pathogenic based on the high‑accuracy predictions, a conclusion that contradicts its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | Uncertain | 2 | -14.545 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.06 | Likely Benign | 0.1 | 0.37 | Likely Benign | 0.22 | Likely Benign | 0.41 | Likely Benign | 0.435 | Likely Benign | -3.58 | Deleterious | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.40 | Benign | 0.12 | Tolerated | 3.37 | 35 | 0.1940 | 0.6392 | 0 | 1 | -0.4 | -0.94 | 206.8 | 52.1 | -0.3 | 0.1 | 0.2 | 0.0 | X | X | Uncertain | Glu486 is located in an α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. It is adjacent to the arginine finger (Arg485) and is expected to closely interact with Ras. The residue swap could affect complex formation with the GTPase and its activation. In the WT simulations, the carboxylate group of Glu486 forms salt bridges with Arg485 and Arg475 on the preceding α-helix (res. Ala461-Phe476). In the variant simulations, Lys486 does not form any specific interactions. Although the amino group of the Lys486 side chain cannot form these salt bridges, no negative effects on the protein structure are observed. Nevertheless, the potential role of Glu486 in SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations, and no definite conclusions can be drawn. | |||||||||||||||
| 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.2077C>A | H693N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693N is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL and FATHMM, whereas the majority of other in silico predictors—premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—label it pathogenic. FoldX, Rosetta, and Foldetta provide uncertain results. High‑accuracy methods specifically give AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for H693N, 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 | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -12.275 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 1.74 | Ambiguous | 0.1 | 0.80 | Ambiguous | 1.27 | Ambiguous | 1.28 | Destabilizing | 0.436 | Likely Benign | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 3.10 | Benign | 0.01 | Affected | 0.1380 | 0.1849 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.845G>C | C282S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign 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 | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -11.846 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.1 | 1.23 | Ambiguous | 1.39 | Ambiguous | 1.62 | Destabilizing | 0.436 | Likely Benign | -9.19 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.64 | Pathogenic | 0.03 | Affected | 3.39 | 18 | 0.5009 | 0.1286 | Weaken | 0 | -1 | -3.3 | -16.06 | 233.2 | 14.8 | -0.1 | 0.0 | -0.2 | 0.3 | X | Potentially Benign | The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), packs against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the hydroxyl-containing side chain of Ser282 is more hydrophilic and, hence, not as favorable as Cys282 for this hydrophobic niche. Due to this polarity difference, the residue swap could potentially weaken the hydrophobic packing of the C2 domain during the folding process.Moreover, because the C2 domain interacts with the membrane, there could also be a negative effect on the stability of the SynGAP-membrane association. However, no large-scale structural changes were observed during the variant simulations. The hydroxyl group of Ser282 forms a hydrogen bond with the backbone carbonyl group of His326 in another β strand (res. Ala322-Arg329), which competes directly with the backbone amide group of Glu283 within the secondary structure element. | |||||||||||||||||
| c.863A>G | D288G 2D 3DClick to see structure in 3D Viewer AISynGAP1 D288G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, 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 as benign. No folding‑stability result is available from FoldX. Overall, the balance of evidence slightly favors a pathogenic interpretation, with one high‑accuracy tool supporting benignity. The prediction 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. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -8.531 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | -0.71 | Ambiguous | 0.4 | 0.21 | Likely Benign | -0.25 | Likely Benign | -0.15 | Likely Benign | 0.436 | Likely Benign | -5.03 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.05 | Pathogenic | 0.13 | Tolerated | 0.4126 | 0.5934 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| 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.2159A>T | D720V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D720V has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Foldetta, and premPS, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -12.730 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.0 | -0.78 | Ambiguous | -0.35 | Likely Benign | 0.20 | Likely Benign | 0.437 | Likely Benign | -7.18 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.12 | Pathogenic | 0.00 | Affected | 0.0822 | 0.5708 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.3416A>C | Q1139P 2D AIThe SynGAP1 missense variant Q1139P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv and SIFT 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 further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, 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 Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -3.753 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.437 | Likely Benign | -1.74 | Neutral | 0.812 | Possibly Damaging | 0.396 | Benign | 5.28 | Benign | 0.00 | Affected | 0.2199 | 0.5349 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3601G>A | E1201K 2D AIThe SynGAP1 missense variant E1201K is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, 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 reports a likely pathogenic status. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the preponderance of computational evidence indicates that E1201K 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 | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -10.090 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.437 | Likely Benign | -3.27 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.63 | Pathogenic | 0.02 | Affected | 0.1539 | 0.5812 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3151G>C | G1051R 2D AIThe SynGAP1 missense variant G1051R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. Two tools (ESM1b and AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it contains one pathogenic, one benign, and two uncertain calls, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -7.907 | In-Between | 0.346 | Ambiguous | Likely Benign | 0.438 | Likely Benign | 0.20 | Neutral | 0.761 | Possibly Damaging | 0.305 | Benign | -0.74 | Pathogenic | 0.20 | Tolerated | 0.0956 | 0.4342 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||||
| c.3626T>G | L1209R 2D AIThe SynGAP1 missense variant L1209R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, 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 reports a likely pathogenic status. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its influence is unavailable. Overall, the preponderance of evidence from multiple prediction tools and high‑accuracy methods indicates that the variant is most likely pathogenic, with no conflict from ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.595080 | Disordered | 0.583711 | Binding | 0.899 | 0.574 | 0.375 | -17.481 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.438 | Likely Benign | -5.12 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.46 | Pathogenic | 0.00 | Affected | 0.1129 | 0.0558 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.868C>A | L290M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, and PROVEAN, whereas pathogenic predictions are reported by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Tools with uncertain outcomes include Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta. High‑accuracy analyses indicate that AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the majority of evidence leans toward a pathogenic effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.399723 | Uncertain | 0.904 | 0.255 | 0.000 | -8.393 | Likely Pathogenic | 0.901 | Likely Pathogenic | Ambiguous | 0.48 | Likely Benign | 0.2 | 0.98 | Ambiguous | 0.73 | Ambiguous | 0.59 | Ambiguous | 0.438 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.92 | Pathogenic | 0.02 | Affected | 0.0823 | 0.4167 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.878G>A | R293H 2D  AISynGAP1 missense variant R293H is listed in ClinVar with an uncertain significance (ClinVar ID 3901513.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL and premPS, whereas the remaining 13 tools—FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies the variant as pathogenic. Overall, the preponderance of evidence indicates that R293H is most likely pathogenic, a conclusion that does not contradict the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.338192 | Uncertain | 0.924 | 0.269 | 0.125 | Uncertain | 1 | -13.009 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 4.45 | Destabilizing | 2.3 | 2.12 | Destabilizing | 3.29 | Destabilizing | 0.32 | Likely Benign | 0.438 | Likely Benign | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.45 | Pathogenic | 0.04 | Affected | 0.3120 | 0.2573 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||
| 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.959T>G | V320G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two agreement groups: the single benign prediction comes from REVEL, while the pathogenic group includes FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—returns pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Overall, the preponderance of evidence indicates that V320G is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -9.043 | Likely Pathogenic | 0.816 | Likely Pathogenic | Ambiguous | 2.15 | Destabilizing | 1.1 | 1.87 | Ambiguous | 2.01 | Destabilizing | 1.48 | Destabilizing | 0.438 | Likely Benign | -5.74 | Deleterious | 0.958 | Probably Damaging | 0.999 | Probably Damaging | 1.89 | Pathogenic | 0.02 | Affected | 0.1688 | 0.1949 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1151G>A | G384D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G384D is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33438056‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, and AlphaMissense‑Optimized. Those that predict pathogenicity are FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; premPS is uncertain. Separately, the high‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools—including the high‑accuracy methods—indicate a pathogenic effect. This prediction does not contradict any 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 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | 6-33438056-G-A | -9.142 | Likely Pathogenic | 0.610 | Likely Pathogenic | Likely Benign | 2.06 | Destabilizing | 0.5 | 2.15 | Destabilizing | 2.11 | Destabilizing | 0.53 | Ambiguous | 0.439 | Likely Benign | -0.93 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 1.32 | Pathogenic | 0.04 | Affected | 4.32 | 2 | 0.2071 | 0.2235 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||||
| c.1480A>G | I494V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I494V is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438512‑A‑G). Functional prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Pathogenic predictions come from premPS and FATHMM. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign; Foldetta remains uncertain. Overall, the majority of evidence supports a benign effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | Conflicting | 2 | 6-33438512-A-G | 36 | 2.23e-5 | -7.102 | In-Between | 0.112 | Likely Benign | Likely Benign | 1.16 | Ambiguous | 0.0 | 0.71 | Ambiguous | 0.94 | Ambiguous | 1.02 | Destabilizing | 0.439 | Likely Benign | -0.83 | Neutral | 0.278 | Benign | 0.179 | Benign | -1.30 | Pathogenic | 0.07 | Tolerated | 3.37 | 35 | 0.0965 | 0.2491 | 4 | 3 | -0.3 | -14.03 | 248.6 | 29.3 | 0.0 | 0.0 | -1.1 | 0.5 | X | Potentially Benign | The sec-butyl side chain of Ile494, located in an α-helix (res. Leu489-Glu519), packs against hydrophobic residues (e.g., Phe484, Leu465, Trp572, Ala493, Met468) in an inter-helix space (res. Leu489-Glu519 and res. Ala461-Phe476). In the variant simulations, the hydrophobic iso-propyl side chain of Val494, which is of a similar size and has similar physicochemical properties to Ile494 in the WT, resides similarly in the inter-helix hydrophobic space. Thus, no negative effects on the protein structure are observed. | ||||||||||||||
| c.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.2023A>T | N675Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions (six pathogenic vs. four benign) indicate that 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. | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -9.981 | Likely Pathogenic | 0.553 | Ambiguous | Likely Benign | 3.02 | Destabilizing | 1.3 | -0.81 | Ambiguous | 1.11 | Ambiguous | 0.19 | Likely Benign | 0.439 | Likely Benign | -5.86 | Deleterious | 1.000 | Probably Damaging | 0.955 | Probably Damaging | 3.38 | Benign | 0.01 | Affected | 0.0603 | 0.6417 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||
| c.2093A>G | E698G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E698G 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, premPS, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all indicate deleteriousness. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E698G. This prediction aligns with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -10.617 | Likely Pathogenic | 0.786 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.0 | 1.25 | Ambiguous | 0.91 | Ambiguous | 0.29 | Likely Benign | 0.439 | Likely Benign | -6.37 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.2529 | 0.3286 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.3563A>C | D1188A 2D AIThe SynGAP1 D1188A 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, ESM1b, and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This prediction is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -4.369 | Likely Benign | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.439 | Likely Benign | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.45 | Benign | 0.00 | Affected | 0.2768 | 0.4495 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.827C>T | P276L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276L 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, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. FoldX, Rosetta, and Foldetta provide uncertain or unavailable stability results and are therefore not considered evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains unavailable. Overall, the predictions are mixed, with an equal split between benign and pathogenic calls, and the high‑accuracy tools do not yield a definitive verdict. Consequently, the variant is most likely benign based on the current evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.037156 | Structured | 0.338937 | Uncertain | 0.724 | 0.230 | 0.250 | -6.687 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 1.64 | Ambiguous | 0.1 | 0.87 | Ambiguous | 1.26 | Ambiguous | 0.33 | Likely Benign | 0.439 | Likely Benign | -4.92 | Deleterious | 0.961 | Probably Damaging | 0.655 | Possibly Damaging | 1.87 | Pathogenic | 0.01 | Affected | 0.2179 | 0.5650 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| 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.1130T>A | M377K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377K 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, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and Foldetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome, while premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. 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 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | -3.718 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.2 | 4.44 | Destabilizing | 2.32 | Destabilizing | 0.62 | Ambiguous | 0.440 | Likely Benign | -0.26 | Neutral | 0.002 | Benign | 0.003 | Benign | 5.46 | Benign | 0.07 | Tolerated | 0.2423 | 0.1671 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1147G>C | G383R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383R 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, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that agree on a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, Foldetta predicts a pathogenic outcome, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign). Overall, the majority of predictions lean toward pathogenicity, and this 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. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.067 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 4.03 | Destabilizing | 2.3 | 3.36 | Destabilizing | 3.70 | Destabilizing | 0.29 | Likely Benign | 0.440 | Likely Benign | -0.84 | Neutral | 0.498 | Possibly Damaging | 0.119 | Benign | 4.10 | Benign | 0.00 | Affected | 0.1295 | 0.3741 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1663G>T | V555F 2D 3DClick to see structure in 3D Viewer AISynGAP1 V555F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default. 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 benign. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence points to a benign 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 | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -10.965 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | 0.17 | Likely Benign | 0.3 | -2.01 | Stabilizing | -0.92 | Ambiguous | 0.16 | Likely Benign | 0.440 | Likely Benign | -2.85 | Deleterious | 0.011 | Benign | 0.013 | Benign | -1.20 | Pathogenic | 0.16 | Tolerated | 0.0727 | 0.2366 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1700A>T | E567V 2D 3DClick to see structure in 3D Viewer AISynGAP1 E567V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS, SIFT, FATHMM) and pathogenic predictions (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Rosetta alone is inconclusive and treated as unavailable. Overall, the majority of evidence points to a pathogenic effect for E567V, 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 | 0.021816 | Structured | 0.051008 | Uncertain | 0.916 | 0.234 | 0.000 | -15.638 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.1 | 0.59 | Ambiguous | 0.43 | Likely Benign | 0.38 | Likely Benign | 0.440 | Likely Benign | -6.77 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.48 | Benign | 0.06 | Tolerated | 0.0573 | 0.6175 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1867C>T | L623F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L623F 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 REVEL, which scores the variant as benign. All other evaluated tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No predictions are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the lack of a benign signal, 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 | 0.175930 | Structured | 0.060667 | Uncertain | 0.962 | 0.211 | 0.000 | -11.655 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 1.22 | Ambiguous | 0.2 | 0.92 | Ambiguous | 1.07 | Ambiguous | 0.57 | Ambiguous | 0.440 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.02 | Affected | 0.0838 | 0.3016 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2789C>T | P930L 2D AIThe SynGAP1 missense variant P930L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. 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 pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect for P930L, 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 | 0.538167 | Disordered | 0.988036 | Binding | 0.304 | 0.855 | 0.375 | -10.690 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.440 | Likely Benign | -7.25 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.66 | Pathogenic | 0.00 | Affected | 0.2275 | 0.6113 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3435C>A | N1145K 2D  AIThe SynGAP1 missense variant N1145K 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, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.545 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.50 | Benign | 0.03 | Affected | 0.1959 | 0.6018 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3435C>G | N1145K 2D AIThe SynGAP1 missense variant N1145K 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, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign impact. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.545 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.50 | Benign | 0.03 | Affected | 0.1959 | 0.6018 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3479A>T | N1160I 2D  AIThe SynGAP1 missense variant N1160I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from multiple in silico tools indicates that 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 | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -4.996 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.440 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.01 | Affected | 0.0618 | 0.5903 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3502A>T | I1168F 2D  AIThe SynGAP1 missense variant I1168F is not reported in ClinVar and is absent from gnomAD. Prediction tools show a mixed signal: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Considering the majority of individual predictors and the SGM‑Consensus outcome, the variant is most likely benign. 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 Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -3.422 | Likely Benign | 0.879 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -1.21 | Neutral | 0.998 | Probably Damaging | 0.958 | Probably Damaging | 5.45 | Benign | 0.04 | Affected | 0.0616 | 0.3524 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3563A>G | D1188G 2D AIThe SynGAP1 D1188G missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus method SGM, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a tie and is therefore inconclusive. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -5.286 | Likely Benign | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.440 | Likely Benign | -3.69 | Deleterious | 0.997 | Probably Damaging | 0.996 | Probably Damaging | 5.47 | Benign | 0.00 | Affected | 0.2771 | 0.4880 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3773A>C | Q1258P 2D AIThe SynGAP1 missense variant Q1258P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. 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 and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.486429 | Structured | 0.525814 | Binding | 0.859 | 0.577 | 0.250 | -16.904 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.440 | Likely Benign | -4.79 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.95 | Pathogenic | 0.00 | Affected | 0.1727 | 0.4187 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||
| c.1244A>T | E415V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E415V missense variant is not reported in ClinVar or gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts benign. No evidence is missing or inconclusive. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.330366 | Uncertain | 0.915 | 0.236 | 0.000 | -11.182 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.56 | Ambiguous | 0.2 | 0.14 | Likely Benign | 0.35 | Likely Benign | 0.40 | Likely Benign | 0.441 | Likely Benign | -6.52 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.13 | Benign | 0.02 | Affected | 0.0650 | 0.4218 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1295G>A | C432Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C432Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign predictions are reported by REVEL, Rosetta, FATHMM, and Foldetta. Tools with uncertain or missing results (FoldX, premPS) are not considered evidence. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predict pathogenicity, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Overall, the majority of predictions support a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.720 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.62 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.47 | Likely Benign | 0.71 | Ambiguous | 0.441 | Likely Benign | -10.50 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.02 | Affected | 0.0857 | 0.3438 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.2141T>C | L714P 2D AIThe SynGAP1 missense variant L714P 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 remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and 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 preponderance of evidence from these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.562 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.48 | Destabilizing | 1.9 | 13.54 | Destabilizing | 10.51 | Destabilizing | 2.26 | Destabilizing | 0.441 | Likely Benign | -6.44 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.08 | Benign | 0.00 | Affected | 0.3572 | 0.1253 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.2783A>C | Q928P 2D AIThe SynGAP1 missense variant Q928P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Based on the preponderance of pathogenic predictions and the SGM‑Consensus designation, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.986260 | Binding | 0.324 | 0.852 | 0.250 | -6.275 | Likely Benign | 0.832 | Likely Pathogenic | Ambiguous | 0.441 | Likely Benign | -4.28 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.54 | Pathogenic | 0.00 | Affected | 0.2016 | 0.5768 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3568A>C | S1190R 2D AIThe SynGAP1 missense variant S1190R is not reported in ClinVar and is absent from gnomAD. Prediction tools show a split assessment: benign calls come from REVEL, PROVEAN, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Grouping by consensus, four tools predict benign and five predict pathogenic. High‑accuracy methods give further contrast: AlphaMissense‑Optimized labels the variant as pathogenic, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a pathogenic interpretation, but the presence of strong benign predictions and the lack of a ClinVar classification mean the variant remains uncertain. No contradiction exists with ClinVar status, as no ClinVar entry is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | -5.258 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.441 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.26 | Benign | 0.05 | Affected | 0.0939 | 0.2997 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| 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.1012G>A | D338N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D338N 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, premPS, and polyPhen‑2 HumVar, whereas a majority of tools predict pathogenicity: SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Overall, the balance of evidence favors a pathogenic interpretation; this is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -9.520 | Likely Pathogenic | 0.809 | Likely Pathogenic | Ambiguous | 0.95 | Ambiguous | 0.4 | 1.34 | Ambiguous | 1.15 | Ambiguous | 0.06 | Likely Benign | 0.442 | Likely Benign | -3.62 | Deleterious | 0.801 | Possibly Damaging | 0.315 | Benign | 1.71 | Pathogenic | 0.02 | Affected | 0.1399 | 0.5970 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1172G>C | G391A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G391A 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 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, and FATHMM. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -5.712 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 2.02 | Destabilizing | 0.5 | 1.92 | Ambiguous | 1.97 | Ambiguous | 0.11 | Likely Benign | 0.442 | Likely Benign | -0.76 | Neutral | 0.633 | Possibly Damaging | 0.219 | Benign | 1.33 | Pathogenic | 0.19 | Tolerated | 0.3828 | 0.4870 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| 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>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.1430T>G | M477R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M477R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and FATHMM. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain and is not taken as evidence. Overall, the majority of reliable predictors indicate a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.268042 | Structured | 0.408680 | Uncertain | 0.761 | 0.250 | 0.000 | -6.786 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.48 | Likely Benign | 0.2 | 0.77 | Ambiguous | 0.63 | Ambiguous | 1.24 | Destabilizing | 0.442 | Likely Benign | -1.12 | Neutral | 0.720 | Possibly Damaging | 0.242 | Benign | -1.22 | Pathogenic | 0.11 | Tolerated | 0.1901 | 0.0828 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||
| c.1721T>C | L574P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L574P is not reported in ClinVar and is present in gnomAD (6-33440773‑T‑C). Prediction tools that indicate a benign effect include REVEL, PROVEAN, and SIFT, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM Consensus score (likely pathogenic). High‑accuracy methods specifically give a pathogenic verdict: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the 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 | 0.083462 | Structured | 0.026427 | Uncertain | 0.927 | 0.246 | 0.000 | 6-33440773-T-C | -13.394 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.95 | Destabilizing | 0.5 | 9.19 | Destabilizing | 6.07 | Destabilizing | 0.59 | Ambiguous | 0.442 | Likely Benign | -1.05 | Neutral | 1.000 | Probably Damaging | 0.971 | Probably Damaging | -1.29 | Pathogenic | 0.26 | Tolerated | 3.38 | 32 | 0.3811 | 0.0953 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||
| c.2528T>A | M843K 2D AIThe SynGAP1 missense variant M843K 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 REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates it is likely pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that M843K is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.585406 | Disordered | 0.617934 | Binding | 0.327 | 0.854 | 0.375 | -13.256 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | -3.60 | Deleterious | 0.968 | Probably Damaging | 0.969 | Probably Damaging | 2.60 | Benign | 0.00 | Affected | 0.1763 | 0.0940 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3440C>G | T1147R 2D AIThe SynGAP1 missense variant T1147R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this view: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates Likely Benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact for T1147R, 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 Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.234 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.442 | Likely Benign | -2.44 | Neutral | 0.411 | Benign | 0.139 | Benign | 5.46 | Benign | 0.01 | Affected | 0.1014 | 0.2742 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3503T>G | I1168S 2D AISynGAP1 missense variant I1168S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the evidence is split, with an equal number of benign and pathogenic calls, and the high‑accuracy predictions are contradictory. Therefore, the variant is not conclusively predicted to be benign or pathogenic, and there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -2.212 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | -1.46 | Neutral | 0.998 | Probably Damaging | 0.958 | Probably Damaging | 5.67 | Benign | 0.01 | Affected | 0.3247 | 0.1540 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3520G>A | E1174K 2D AIThe SynGAP1 missense variant E1174K is listed in ClinVar with an uncertain significance (ClinVar ID 1905754.0) and is present in gnomAD (variant ID 6‑33444555‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, matching the reported SGM‑Consensus result. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Taken together, 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. | Likely Benign | Coiled-coil | 0.483068 | Structured | 0.618958 | Binding | 0.523 | 0.734 | 0.375 | Uncertain | 1 | 6-33444555-G-A | 2 | 1.24e-6 | -4.345 | Likely Benign | 0.898 | Likely Pathogenic | Ambiguous | 0.442 | Likely Benign | -1.59 | Neutral | 0.962 | Probably Damaging | 0.367 | Benign | 5.52 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1852 | 0.6521 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||
| c.3590A>C | E1197A 2D AIThe SynGAP1 missense variant E1197A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta results are unavailable. Consequently, the evidence is balanced between benign and pathogenic predictions, with no high‑confidence support for either outcome. The variant is most likely benign based on the 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. | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -4.852 | Likely Benign | 0.795 | Likely Pathogenic | Ambiguous | 0.442 | Likely Benign | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.45 | Benign | 0.09 | Tolerated | 0.2811 | 0.5169 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3631A>C | M1211L 2D AIThe SynGAP1 missense variant M1211L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Overall, the preponderance of evidence indicates that M1211L is most likely benign, 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 Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -2.552 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.442 | Likely Benign | -0.76 | Neutral | 0.856 | Possibly Damaging | 0.881 | Possibly Damaging | 5.45 | Benign | 0.14 | Tolerated | 0.1280 | 0.3547 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3631A>T | M1211L 2D AIThe SynGAP1 missense variant M1211L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -2.552 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.442 | Likely Benign | -0.76 | Neutral | 0.856 | Possibly Damaging | 0.881 | Possibly Damaging | 5.45 | Benign | 0.14 | Tolerated | 0.1280 | 0.3547 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3713A>C | Q1238P 2D AIThe SynGAP1 missense variant Q1238P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as pathogenic; Foldetta results are not available. 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 | Coiled-coil | 0.562014 | Disordered | 0.548882 | Binding | 0.855 | 0.545 | 0.250 | -13.929 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.442 | Likely Benign | -4.06 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 2.30 | Pathogenic | 0.01 | Affected | 0.1549 | 0.3619 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||||||
| 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.1198G>A | V400M 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V400M is reported in gnomAD (ID 6‑33438103‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, only three tools—polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default—predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, SGM‑Consensus is likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX or premPS is available. Overall, the preponderance of predictions, including the high‑accuracy methods, supports a benign classification, which is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | 6-33438103-G-A | 3 | 1.86e-6 | -5.438 | Likely Benign | 0.573 | Likely Pathogenic | Likely Benign | -1.12 | Ambiguous | 0.1 | -0.16 | Likely Benign | -0.64 | Ambiguous | 0.55 | Ambiguous | 0.443 | Likely Benign | -1.44 | Neutral | 0.868 | Possibly Damaging | 0.289 | Benign | 5.26 | Benign | 0.01 | Affected | 3.38 | 27 | 0.0851 | 0.4643 | 1 | 2 | -2.3 | 32.06 | ||||||||||||||||||||||||
| 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.1357C>G | H453D 2D 3DClick to see structure in 3D Viewer AISynGAP1 H453D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods reinforce a pathogenic interpretation: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenicity. premPS remains uncertain. Overall, the majority of evidence points to a pathogenic effect for H453D, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.256 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.33 | Destabilizing | 0.0 | 2.68 | Destabilizing | 3.01 | Destabilizing | 0.97 | Ambiguous | 0.443 | Likely Benign | -8.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.48 | Benign | 0.09 | Tolerated | 0.2225 | 0.1815 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| 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.1730C>G | A577G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A577G is listed in ClinVar as Benign (ClinVar ID 1010280.0) and is present in gnomAD (ID 6‑33440782‑C‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy methods give a benign verdict: AlphaMissense‑Optimized is benign, the SGM‑Consensus is Likely Benign, and Foldetta is uncertain. Overall, the majority of reliable predictions support a benign impact, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.113710 | Structured | 0.019074 | Uncertain | 0.913 | 0.239 | 0.000 | Benign/Likely benign | 2 | 6-33440782-C-G | 1 | 6.20e-7 | -5.717 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.0 | 1.02 | Ambiguous | 0.93 | Ambiguous | 0.86 | Ambiguous | 0.443 | Likely Benign | -1.84 | Neutral | 0.997 | Probably Damaging | 0.990 | Probably Damaging | -1.31 | Pathogenic | 0.31 | Tolerated | 3.37 | 34 | 0.2120 | 0.3780 | 1 | 0 | -2.2 | -14.03 | 158.7 | 23.6 | 0.0 | 0.0 | 0.0 | 0.0 | X | Potentially Benign | Ala577 is located near the end and outer surface of an α-helix (res. Arg563-Glu578), where its methyl group does not form any particular interactions in the WT simulations. The introduced residue, glycine, is known as an “α-helix breaker.” However, the residue swap caused only minor helix shortening in one of the replica simulations for the variant system. Regardless, the residue swap seems to be well tolerated based on the variant simulations. | |||||||||||||
| c.3122C>G | P1041R 2D AIThe SynGAP1 missense variant P1041R 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, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The AlphaMissense‑Default result is uncertain, and no Foldetta stability data are available, so these are treated as unavailable. Overall, six tools support a benign classification while three support pathogenicity, and the high‑accuracy AlphaMissense‑Optimized and SGM Consensus both predict benign. Therefore, the variant is most likely benign based on the current predictions, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -4.808 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 0.443 | Likely Benign | -3.33 | Deleterious | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 5.46 | Benign | 0.07 | Tolerated | 0.1401 | 0.4292 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3518T>A | I1173N 2D AIThe SynGAP1 missense variant I1173N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also leans benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Taken together, the preponderance of evidence points to a benign impact for I1173N, 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 | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -4.130 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.443 | Likely Benign | -1.46 | Neutral | 0.925 | Possibly Damaging | 0.611 | Possibly Damaging | 5.34 | Benign | 0.02 | Affected | 0.0920 | 0.0142 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3655T>G | Y1219D 2D AIThe SynGAP1 missense variant Y1219D is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—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 predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta results are not available for this variant. Based on the preponderance of pathogenic predictions, Y1219D 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 | Coiled-coil | 0.613573 | Disordered | 0.474748 | Uncertain | 0.855 | 0.557 | 0.375 | -15.860 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.443 | Likely Benign | -7.11 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.4549 | 0.0573 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.3767A>C | D1256A 2D AIThe SynGAP1 D1256A missense change 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 REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic impact. 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 pathogenic and the SGM‑Consensus as likely pathogenic; Foldetta results are not available. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.549308 | Disordered | 0.445789 | Uncertain | 0.876 | 0.571 | 0.625 | -11.665 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.443 | Likely Benign | -6.06 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.2830 | 0.4451 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||
| c.847G>A | E283K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL and FoldX, whereas the majority of algorithms predict it to be pathogenic: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain results come from Rosetta, Foldetta, and premPS. 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; 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 | 0.098513 | Structured | 0.358602 | Uncertain | 0.950 | 0.249 | 0.000 | -14.350 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.1 | 0.82 | Ambiguous | 0.56 | Ambiguous | 0.62 | Ambiguous | 0.443 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.92 | Pathogenic | 0.01 | Affected | 0.2989 | 0.5714 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.1058T>G | L353R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353R is not reported in ClinVar and is absent from gnomAD. In silico predictors largely agree on a deleterious effect: benign predictions are limited to REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all classify the variant as pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized is uncertain, SGM‑Consensus predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction contradicts the ClinVar status, which is currently unreported. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -11.213 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 3.60 | Destabilizing | 0.5 | 2.48 | Destabilizing | 3.04 | Destabilizing | 1.91 | Destabilizing | 0.444 | Likely Benign | -4.15 | Deleterious | 0.947 | Possibly Damaging | 0.454 | Possibly Damaging | 1.33 | Pathogenic | 0.01 | Affected | 0.1304 | 0.1145 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1952A>G | E651G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E651G 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 PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are uncertain or unavailable are FoldX, Rosetta, ESM1b, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as unavailable. Overall, the majority of tools (five benign vs. four pathogenic) lean toward a benign interpretation, and this does not contradict the lack of ClinVar annotation. Thus, based on the available predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -7.596 | In-Between | 0.591 | Likely Pathogenic | Likely Benign | 0.66 | Ambiguous | 0.1 | 1.61 | Ambiguous | 1.14 | Ambiguous | 0.32 | Likely Benign | 0.444 | Likely Benign | -4.78 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.31 | Benign | 0.06 | Tolerated | 0.2908 | 0.4488 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.2039A>C | E680A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E680A 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, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of predictions lean toward pathogenicity, but the conflicting high‑accuracy results leave the classification uncertain. The variant is most likely pathogenic based on the prevailing evidence, and this assessment does not contradict the ClinVar status, which currently has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -11.338 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.2 | 0.59 | Ambiguous | 0.47 | Likely Benign | 0.30 | Likely Benign | 0.444 | Likely Benign | -5.22 | Deleterious | 0.935 | Possibly Damaging | 0.490 | Possibly Damaging | 3.47 | Benign | 0.09 | Tolerated | 0.3931 | 0.6989 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.2158G>C | D720H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720H missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, and premPS. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and is labeled Likely Pathogenic. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, indicates a Benign effect. Considering the overall distribution of predictions, 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 | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -12.355 | Likely Pathogenic | 0.947 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | -0.87 | Ambiguous | -0.42 | Likely Benign | 0.48 | Likely Benign | 0.444 | Likely Benign | -5.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.13 | Pathogenic | 0.01 | Affected | 0.1363 | 0.6198 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.2777C>A | S926Y 2D AIThe SynGAP1 missense variant S926Y 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 and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. High‑accuracy assessments reinforce this trend: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for S926Y, 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 | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.602 | Likely Benign | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.444 | Likely Benign | -4.53 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0602 | 0.4932 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.3127A>T | R1043W 2D  AIThe SynGAP1 missense variant R1043W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction; Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -6.382 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.444 | Likely Benign | -3.43 | Deleterious | 0.971 | Probably Damaging | 0.729 | Possibly Damaging | 5.38 | Benign | 0.00 | Affected | 0.1403 | 0.3696 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3659A>T | E1220V 2D AIThe SynGAP1 missense variant E1220V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that E1220V 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 | Coiled-coil | 0.703578 | Disordered | 0.444845 | Uncertain | 0.881 | 0.551 | 0.375 | -15.193 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.444 | Likely Benign | -6.05 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.59 | Pathogenic | 0.00 | Affected | 0.0552 | 0.4452 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.787G>A | V263M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts Benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) reports Benign. No conflicting evidence is present. **Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -5.956 | Likely Benign | 0.218 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.1 | -0.24 | Likely Benign | -0.02 | Likely Benign | 0.43 | Likely Benign | 0.444 | Likely Benign | -0.95 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.84 | Benign | 0.03 | Affected | 0.0665 | 0.3545 | 2 | 1 | -2.3 | 32.06 | |||||||||||||||||||||||||||||
| c.790C>G | L264V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and AlphaMissense‑Optimized; all other evaluated algorithms (SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic or likely pathogenic outcome, while Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic interpretation: 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) classifies the variant as Pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for L264V, 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 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | -10.621 | Likely Pathogenic | 0.630 | Likely Pathogenic | Likely Benign | 2.55 | Destabilizing | 0.1 | 1.62 | Ambiguous | 2.09 | Destabilizing | 1.24 | Destabilizing | 0.444 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 0.73 | Pathogenic | 0.01 | Affected | 0.1280 | 0.2289 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.978T>A | H326Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, whereas a majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Foldetta (combining FoldX‑MD and Rosetta) and Rosetta alone, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for H326Q. 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 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -8.688 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.67 | Ambiguous | 1.07 | Ambiguous | 1.00 | Destabilizing | 0.444 | Likely Benign | -6.89 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.07 | Pathogenic | 0.10 | Tolerated | 0.1485 | 0.3500 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.978T>G | H326Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, whereas a majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Foldetta (combining FoldX‑MD and Rosetta) and Rosetta alone, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also indicates likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for H326Q. 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 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -8.688 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.67 | Ambiguous | 1.07 | Ambiguous | 1.00 | Destabilizing | 0.444 | Likely Benign | -6.89 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.07 | Pathogenic | 0.10 | Tolerated | 0.1485 | 0.3500 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.997A>C | K333Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K333Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, while those that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Tools with inconclusive results are AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign (combining FoldX‑MD and Rosetta outputs). Overall, the majority of evidence points toward a pathogenic classification, which 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 | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -11.647 | Likely Pathogenic | 0.866 | Likely Pathogenic | Ambiguous | 0.00 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.26 | Likely Benign | 0.76 | Ambiguous | 0.444 | Likely Benign | -3.11 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.08 | Tolerated | 0.4015 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1207A>G | K403E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for K403E, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -15.279 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.01 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.90 | Ambiguous | 0.70 | Ambiguous | 0.445 | Likely Benign | -3.62 | Deleterious | 0.998 | Probably Damaging | 0.981 | Probably Damaging | 3.79 | Benign | 0.04 | Affected | 0.3650 | 0.1715 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1502T>A | I501N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, while a majority of tools (SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Uncertain results come from AlphaMissense‑Optimized, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, whereas the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta likewise remains inconclusive. Overall, the balance of evidence favors a pathogenic classification, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -11.105 | Likely Pathogenic | 0.854 | Likely Pathogenic | Ambiguous | 2.22 | Destabilizing | 0.0 | 1.70 | Ambiguous | 1.96 | Ambiguous | 1.90 | Destabilizing | 0.445 | Likely Benign | -6.13 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.0825 | 0.0270 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.3151G>A | G1051S 2D AIThe SynGAP1 missense variant G1051S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. When the predictions are grouped, the benign consensus includes eight tools, whereas the pathogenic consensus contains a single tool. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a likely benign outcome. Foldetta data are unavailable, so no stability inference can be drawn. Overall, the computational evidence overwhelmingly supports a benign classification for G1051S, and this conclusion is consistent with the absence of any ClinVar annotation. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -4.742 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.445 | Likely Benign | 0.10 | Neutral | 0.245 | Benign | 0.096 | Benign | -0.74 | Pathogenic | 0.61 | Tolerated | 0.2446 | 0.4911 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3152G>A | G1051D 2D AISynGAP1 missense variant G1051D is listed in ClinVar as Benign and is present in gnomAD (variant ID 6‑33443704‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign versus two pathogenic votes), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign effect, consistent with the ClinVar annotation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | Benign | 1 | 6-33443704-G-A | 2 | 1.24e-6 | -9.379 | Likely Pathogenic | 0.311 | Likely Benign | Likely Benign | 0.445 | Likely Benign | -0.31 | Neutral | 0.761 | Possibly Damaging | 0.239 | Benign | -0.74 | Pathogenic | 0.39 | Tolerated | 3.77 | 5 | 0.1872 | 0.2235 | -1 | 1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||
| c.727A>G | I243V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243V 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, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. FoldX and Foldetta give uncertain 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 remains uncertain. Overall, the majority of evidence points to a benign impact. 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 Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -8.237 | Likely Pathogenic | 0.314 | Likely Benign | Likely Benign | 1.09 | Ambiguous | 0.1 | 0.19 | Likely Benign | 0.64 | Ambiguous | 0.39 | Likely Benign | 0.445 | Likely Benign | -0.39 | Neutral | 0.617 | Possibly Damaging | 0.140 | Benign | 5.71 | Benign | 0.15 | Tolerated | 0.1019 | 0.2591 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.1162G>A | G388S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G388S is catalogued in gnomAD (ID 6‑33438067‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that converge on a pathogenic interpretation are FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. In contrast, the protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, indicates a pathogenic effect. No prediction is available from Rosetta alone, and the SGM‑Consensus result aligns with the benign consensus. Overall, the majority of evidence points to a benign impact, 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 Benign | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | 6-33438067-G-A | 1 | 6.21e-7 | -5.036 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 3.42 | Destabilizing | 3.5 | 1.69 | Ambiguous | 2.56 | Destabilizing | 0.18 | Likely Benign | 0.446 | Likely Benign | -0.52 | Neutral | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 1.33 | Pathogenic | 0.05 | Affected | 4.32 | 3 | 0.2901 | 0.4985 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||
| c.1180A>G | K394E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K394E is not listed in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438085‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Those that predict a pathogenic effect are premPS, PROVEAN, SIFT, 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 2‑vs‑2 tie, and Foldetta is uncertain. No prediction or folding‑stability result is available that decisively supports either outcome. Overall, the majority of tools (six benign vs four pathogenic) lean toward a benign interpretation, and this assessment does not contradict the absence of a ClinVar classification. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | 6-33438085-A-G | 1 | 6.20e-7 | -6.903 | Likely Benign | 0.896 | Likely Pathogenic | Ambiguous | 0.07 | Likely Benign | 0.1 | 3.71 | Destabilizing | 1.89 | Ambiguous | 1.20 | Destabilizing | 0.446 | Likely Benign | -2.54 | Deleterious | 0.063 | Benign | 0.038 | Benign | 4.61 | Benign | 0.04 | Affected | 3.44 | 14 | 0.4556 | 0.1916 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1412C>A | S471Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, premPS, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized scores the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it as likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, returns an uncertain stability change. No evidence from ClinVar contradicts these computational assessments. Overall, the preponderance of pathogenic predictions and the SGM Consensus suggest the variant is most likely pathogenic, consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -11.257 | Likely Pathogenic | 0.493 | Ambiguous | Likely Benign | -0.33 | Likely Benign | 0.1 | -1.31 | Ambiguous | -0.82 | Ambiguous | 0.19 | Likely Benign | 0.446 | Likely Benign | -4.79 | Deleterious | 0.980 | Probably Damaging | 0.584 | Possibly Damaging | -1.27 | Pathogenic | 0.03 | Affected | 0.0607 | 0.4417 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.2831G>T | G944V 2D AIThe SynGAP1 missense variant G944V is catalogued in gnomAD (ID 6‑33443383‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the substitution as benign or likely benign. Only SIFT predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates a likely benign status. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the collective evidence points to a benign variant, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this assessment does not contradict its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | 6-33443383-G-T | 1 | 6.20e-7 | -7.536 | In-Between | 0.090 | Likely Benign | Likely Benign | 0.446 | Likely Benign | -1.41 | Neutral | 0.126 | Benign | 0.096 | Benign | 3.70 | Benign | 0.00 | Affected | 4.32 | 4 | 0.1455 | 0.3507 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.3175G>T | G1059W 2D AIThe SynGAP1 missense variant G1059W 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack 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 Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -11.549 | Likely Pathogenic | 0.312 | Likely Benign | Likely Benign | 0.446 | Likely Benign | -1.18 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 2.53 | Benign | 0.00 | Affected | 0.0925 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3767A>T | D1256V 2D AIThe SynGAP1 missense variant D1256V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact largely agree on a deleterious effect: SIFT, polyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while the only benign prediction comes from REVEL. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Pathogenic.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status. Foldetta results are not available, so they do not influence the overall assessment. 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 | Coiled-coil | 0.549308 | Disordered | 0.445789 | Uncertain | 0.876 | 0.571 | 0.625 | -14.067 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.446 | Likely Benign | -6.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.63 | Pathogenic | 0.00 | Affected | 0.0573 | 0.4407 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||
| c.1157G>A | G386E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G386E is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438062‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, Foldetta, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Overall, the majority of tools predict a pathogenic impact, suggesting the variant is most likely pathogenic, which does not contradict the ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | Uncertain | 1 | 6-33438062-G-A | -9.286 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | 3.69 | Destabilizing | 2.9 | 0.79 | Ambiguous | 2.24 | Destabilizing | 0.54 | Ambiguous | 0.447 | Likely Benign | -0.83 | Neutral | 0.860 | Possibly Damaging | 0.354 | Benign | 3.93 | Benign | 0.01 | Affected | 4.32 | 3 | 0.1543 | 0.3354 | -2 | 0 | -3.1 | 72.06 | |||||||||||||||||||||||||
| c.1679T>C | V560A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V560A is not reported in ClinVar (ClinVar status: none) and has no entry in gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive 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 pathogenic; Foldetta remains uncertain. Overall, the majority of predictions (eight pathogenic vs. three benign) indicate that 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 | GAP | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | -8.260 | Likely Pathogenic | 0.701 | Likely Pathogenic | Likely Benign | 0.54 | Ambiguous | 0.1 | 1.33 | Ambiguous | 0.94 | Ambiguous | 1.19 | Destabilizing | 0.447 | Likely Benign | -3.15 | Deleterious | 0.911 | Possibly Damaging | 0.657 | Possibly Damaging | -1.20 | Pathogenic | 0.31 | Tolerated | 0.2549 | 0.2212 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.2150T>C | L717P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L717P 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, while the remaining 13 tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) all classify the variant as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.429342 | Uncertain | 0.969 | 0.397 | 0.000 | -10.214 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.96 | Destabilizing | 0.2 | 6.56 | Destabilizing | 5.26 | Destabilizing | 1.66 | Destabilizing | 0.447 | Likely Benign | -5.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.28 | Benign | 0.00 | Affected | 0.3065 | 0.1053 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.3709T>G | Y1237D 2D AIThe SynGAP1 missense variant Y1237D 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 only REVEL, which scores the variant as benign. All other evaluated predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, 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 reports the variant as likely pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status. Foldetta results are unavailable, so no additional folding‑stability evidence is provided. Overall, the preponderance of predictions indicates that 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 | Coiled-coil | 0.653063 | Disordered | 0.563444 | Binding | 0.842 | 0.535 | 0.125 | -12.849 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.447 | Likely Benign | -8.04 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.44 | Pathogenic | 0.00 | Affected | 0.4353 | 0.0173 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| 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.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.3155G>A | G1052E 2D AIThe SynGAP1 missense variant G1052E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral impact. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign classification, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -9.869 | Likely Pathogenic | 0.287 | Likely Benign | Likely Benign | 0.448 | Likely Benign | -0.64 | Neutral | 0.901 | Possibly Damaging | 0.537 | Possibly Damaging | 3.90 | Benign | 0.12 | Tolerated | 0.1405 | 0.3873 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.3167G>T | G1056V 2D AIThe SynGAP1 missense variant G1056V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence (7 benign vs 2 pathogenic) supports a benign classification. This consensus does not contradict ClinVar status, which has no entry for this variant. 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. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -8.130 | Likely Pathogenic | 0.097 | Likely Benign | Likely Benign | 0.448 | Likely Benign | -0.24 | Neutral | 0.292 | Benign | 0.110 | Benign | 1.83 | Pathogenic | 0.08 | Tolerated | 0.1488 | 0.3507 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3626T>C | L1209P 2D AIThe SynGAP1 missense variant L1209P 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 REVEL, which scores the variant as benign. All other evaluated tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as pathogenic; Foldetta results are unavailable. Based on the overwhelming agreement among pathogenic predictions and the lack of benign 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 | Coiled-coil | 0.595080 | Disordered | 0.583711 | Binding | 0.899 | 0.574 | 0.375 | -17.259 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.448 | Likely Benign | -5.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.45 | Pathogenic | 0.00 | Affected | 0.3646 | 0.1053 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| c.3632T>C | M1211T 2D AIThe SynGAP1 missense variant M1211T 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, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those predicting pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -3.885 | Likely Benign | 0.669 | Likely Pathogenic | Likely Benign | 0.448 | Likely Benign | -1.99 | Neutral | 0.987 | Probably Damaging | 0.968 | Probably Damaging | 5.54 | Benign | 0.02 | Affected | 0.1987 | 0.1614 | -1 | -1 | -2.6 | -30.09 | ||||||||||||||||||||||||||||||||||||||
| c.1147G>A | G383R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383R 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, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that agree on a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, Foldetta predicts a pathogenic outcome, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign). Overall, the majority of predictions lean toward pathogenicity, and this 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. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.067 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 4.03 | Destabilizing | 2.3 | 3.36 | Destabilizing | 3.70 | Destabilizing | 0.29 | Likely Benign | 0.449 | Likely Benign | -0.84 | Neutral | 0.498 | Possibly Damaging | 0.119 | Benign | 4.10 | Benign | 0.00 | Affected | 0.1295 | 0.3741 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1667A>G | N556S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N556S (ClinVar ID 941099.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33438910‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, 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. The high‑accuracy AlphaMissense‑Optimized score is 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 effect. No other high‑accuracy or folding‑stability methods provide additional evidence. Overall, the majority of predictions support 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. | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | Uncertain | 1 | 6-33438910-A-G | 3 | 1.86e-6 | -6.576 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.52 | Ambiguous | 0.1 | 0.14 | Likely Benign | 0.33 | Likely Benign | 0.16 | Likely Benign | 0.449 | Likely Benign | -3.60 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | -1.22 | Pathogenic | 0.14 | Tolerated | 3.37 | 35 | 0.2641 | 0.3556 | 1 | 1 | 2.7 | -27.03 | 198.8 | 31.0 | 0.0 | 0.0 | -0.5 | 0.2 | X | Potentially Benign | Asn556 is located on the outer surface of an α-helix (res. Ala533-Val560). The carboxamide group of Asn556 forms hydrogen bonds with nearby residues such as Lys553 and Cys552. It also forms a hydrogen bond with the backbone carbonyl group of Cys552, which weakens the α-helix integrity. In the variant simulations, the hydroxyl group of Ser556 forms a more stable hydrogen bond with the backbone carbonyl oxygen of the same helix residue, Cys552, compared to Asn556 in the WT. Serine has a slightly lower propensity to reside in an α-helix than asparagine, which may exacerbate the negative effect on the α-helix integrity. However, the residue swap does not cause negative structural effects during the simulations. | ||||||||||||||
| 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.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.1947G>A | M649I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M649I has no ClinVar entry 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 (SGM‑Consensus, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta is inconclusive and is not counted. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Taken together, the preponderance of evidence supports a pathogenic classification for M649I, and this conclusion does not conflict with ClinVar status, which is currently unavailable. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -9.361 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.42 | Destabilizing | 0.2 | 1.96 | Ambiguous | 2.19 | Destabilizing | 1.01 | Destabilizing | 0.449 | Likely Benign | -3.99 | Deleterious | 0.672 | Possibly Damaging | 0.093 | Benign | 3.40 | Benign | 0.02 | Affected | 3.38 | 27 | 0.1215 | 0.2980 | 2 | 1 | 2.6 | -18.03 | 243.7 | 21.5 | 0.0 | 0.1 | 0.0 | 0.1 | X | Potentially Benign | The thioether side chain of Met649, located on an α helix (res. Ser641-Glu666), bridges Phe652, Phe648, and Phe639 in an inter-helix hydrophobic cavity in the WT simulations. In the variant simulations, the sec-butyl side chain of Ile649 maintains hydrophobic interactions with nearby residues, with no significant effects on the protein structure.However, methionine is known as a bridging motif for aromatic residues, and these Met-aromatic interactions are lost in the variant. Indeed, in the second variant simulation,the bridging of Phe652, Phe648 and Phe639 is completely lost. In reality, the effect could be more severe on the structure during the protein folding. | ||||||||||||||||||
| c.1947G>C | M649I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of other in silico predictors (FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) report a pathogenic outcome; Rosetta is inconclusive. High‑accuracy assessments further support a deleterious impact: 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. Overall, the preponderance of evidence points to a pathogenic effect for M649I, which is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | Uncertain | 1 | -9.361 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.42 | Destabilizing | 0.2 | 1.96 | Ambiguous | 2.19 | Destabilizing | 1.01 | Destabilizing | 0.449 | Likely Benign | -3.99 | Deleterious | 0.672 | Possibly Damaging | 0.093 | Benign | 3.40 | Benign | 0.02 | Affected | 3.38 | 27 | 0.1215 | 0.2980 | 2 | 1 | 2.6 | -18.03 | 243.7 | 21.5 | 0.0 | 0.1 | 0.0 | 0.1 | X | Potentially Benign | The thioether side chain of Met649, located on an α helix (res. Ser641-Glu666), bridges Phe652, Phe648, and Phe639 in an inter-helix hydrophobic cavity in the WT simulations. In the variant simulations, the sec-butyl side chain of Ile649 maintains hydrophobic interactions with nearby residues, with no significant effects on the protein structure.However, methionine is known as a bridging motif for aromatic residues, and these Met-aromatic interactions are lost in the variant. Indeed, in the second variant simulation,the bridging of Phe652, Phe648 and Phe639 is completely lost. In reality, the effect could be more severe on the structure during the protein folding. | ||||||||||||||||
| c.1947G>T | M649I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic calls are made by FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, votes strongly for pathogenicity (3/4 pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts pathogenic. Rosetta alone is uncertain and is treated as unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -9.361 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.42 | Destabilizing | 0.2 | 1.96 | Ambiguous | 2.19 | Destabilizing | 1.01 | Destabilizing | 0.449 | Likely Benign | -3.99 | Deleterious | 0.672 | Possibly Damaging | 0.093 | Benign | 3.40 | Benign | 0.02 | Affected | 3.38 | 27 | 0.1215 | 0.2980 | 2 | 1 | 2.6 | -18.03 | 243.7 | 21.5 | 0.0 | 0.1 | 0.0 | 0.1 | X | Potentially Benign | The thioether side chain of Met649, located on an α helix (res. Ser641-Glu666), bridges Phe652, Phe648, and Phe639 in an inter-helix hydrophobic cavity in the WT simulations. In the variant simulations, the sec-butyl side chain of Ile649 maintains hydrophobic interactions with nearby residues, with no significant effects on the protein structure.However, methionine is known as a bridging motif for aromatic residues, and these Met-aromatic interactions are lost in the variant. Indeed, in the second variant simulation,the bridging of Phe652, Phe648 and Phe639 is completely lost. In reality, the effect could be more severe on the structure during the protein folding. | ||||||||||||||||||
| c.3376G>T | G1126C 2D AIThe SynGAP1 missense variant G1126C is listed in ClinVar (ID 469157.0) with an “Uncertain” status and is present in gnomAD (6‑33443928‑G‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are SIFT and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | Uncertain | 1 | 6-33443928-G-T | 11 | 7.35e-6 | -9.389 | Likely Pathogenic | 0.113 | Likely Benign | Likely Benign | 0.449 | Likely Benign | -1.40 | Neutral | 0.005 | Benign | 0.005 | Benign | 4.74 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1326 | 0.4427 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||
| c.1111A>T | S371C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371C 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, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the majority 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 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -6.330 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.19 | Likely Benign | 0.2 | -0.34 | Likely Benign | -0.08 | Likely Benign | 0.23 | Likely Benign | 0.450 | Likely Benign | -1.41 | Neutral | 0.875 | Possibly Damaging | 0.359 | Benign | 4.61 | Benign | 0.02 | Affected | 0.1786 | 0.6580 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.1123G>T | G375W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375W is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438028‑G‑T). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; 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 pathogenic. Overall, the majority of evidence, including the high‑accuracy tools, points to a pathogenic effect for G375W. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | 6-33438028-G-T | -9.654 | Likely Pathogenic | 0.464 | Ambiguous | Likely Benign | 4.33 | Destabilizing | 2.0 | 7.01 | Destabilizing | 5.67 | Destabilizing | 0.22 | Likely Benign | 0.450 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.869 | Possibly Damaging | 1.31 | Pathogenic | 0.01 | Affected | 4.32 | 12 | 0.0992 | 0.4368 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||||
| c.1675T>A | C559S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C559S 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, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The remaining tools, 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) as Benign. Based on the overall distribution of predictions, the variant is most likely pathogenic; this conclusion does not contradict the ClinVar status, which has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -10.756 | Likely Pathogenic | 0.785 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.0 | -0.31 | Likely Benign | -0.17 | Likely Benign | 0.65 | Ambiguous | 0.450 | Likely Benign | -7.26 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.58 | Benign | 0.64 | Tolerated | 0.3940 | 0.1319 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1732G>A | E578K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E578K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and SIFT, whereas polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default predict a pathogenic outcome. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic, AlphaMissense‑Optimized remains Uncertain, and Foldetta predicts a benign effect. Overall, the majority of tools (seven benign vs. five pathogenic) suggest a benign impact, and this assessment does not contradict the absence of ClinVar evidence. Thus, the variant is most likely benign based on the current predictions, with no conflicting ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.059222 | Structured | 0.020971 | Uncertain | 0.902 | 0.240 | 0.000 | -13.391 | Likely Pathogenic | 0.870 | Likely Pathogenic | Ambiguous | 0.07 | Likely Benign | 0.1 | -0.19 | Likely Benign | -0.06 | Likely Benign | -0.27 | Likely Benign | 0.450 | Likely Benign | -1.65 | Neutral | 0.996 | Probably Damaging | 0.987 | Probably Damaging | -1.30 | Pathogenic | 0.49 | Tolerated | 0.1954 | 0.5480 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.470G>C | R157P 2D  AIThe SynGAP1 missense variant R157P 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 REVEL and FATHMM. All other evaluated tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus indicates it is likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; 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 | 0.483068 | Structured | 0.523978 | Binding | 0.306 | 0.777 | 0.375 | -11.463 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.450 | Likely Benign | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.79 | Benign | 0.00 | Affected | 0.2438 | 0.3438 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| 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.1067G>C | R356P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R356P missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FoldX, whereas a majority of tools (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive are AlphaMissense‑Optimized, Rosetta, and Foldetta. 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 R356P, 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 | 0.219301 | Structured | 0.395028 | Uncertain | 0.802 | 0.373 | 0.250 | -12.956 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.48 | Likely Benign | 0.1 | 0.72 | Ambiguous | 0.60 | Ambiguous | 1.05 | Destabilizing | 0.451 | Likely Benign | -6.23 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 1.72 | Pathogenic | 0.02 | Affected | 0.2213 | 0.5033 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| 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.3614T>G | L1205R 2D AIThe SynGAP1 missense variant L1205R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—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, and the SGM‑Consensus (majority vote) is likely pathogenic. Foldetta results are unavailable. Based on the collective predictions, 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 | Coiled-coil | 0.595080 | Disordered | 0.552471 | Binding | 0.880 | 0.576 | 0.375 | -16.706 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.451 | Likely Benign | -5.08 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.46 | Pathogenic | 0.00 | Affected | 0.1081 | 0.0558 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.863A>C | D288A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288A 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, premPS, and SIFT. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized, Foldetta, and Rosetta give uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. Overall, seven tools predict pathogenicity while four predict benign, with no conflicting ClinVar evidence. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -13.470 | Likely Pathogenic | 0.908 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.1 | 1.27 | Ambiguous | 0.81 | Ambiguous | 0.10 | Likely Benign | 0.451 | Likely Benign | -6.09 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.71 | Pathogenic | 0.07 | Tolerated | 0.4060 | 0.5788 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.962G>T | R321L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include SIFT, polyPhen‑2 (HumDiv and HumVar), PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign; FoldX and Rosetta individually are inconclusive. Overall, the majority of predictions lean toward pathogenicity, 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 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -11.709 | Likely Pathogenic | 0.551 | Ambiguous | Likely Benign | 0.54 | Ambiguous | 0.0 | -0.58 | Ambiguous | -0.02 | Likely Benign | 0.18 | Likely Benign | 0.451 | Likely Benign | -4.06 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.93 | Pathogenic | 0.03 | Affected | 0.1745 | 0.4048 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.3155G>T | G1052V 2D AIThe SynGAP1 missense variant G1052V is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign, while the high‑accuracy AlphaMissense‑Optimized score is benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. In contrast, polyPhen‑2 HumDiv and HumVar both predict pathogenic, and ESM1b remains uncertain. No Foldetta stability assessment is available, so it does not influence the overall interpretation. Overall, the majority of evidence points to a benign effect, 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 Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -7.717 | In-Between | 0.094 | Likely Benign | Likely Benign | 0.452 | Likely Benign | -0.12 | Neutral | 0.901 | Possibly Damaging | 0.619 | Possibly Damaging | 3.90 | Benign | 0.19 | Tolerated | 0.1329 | 0.3499 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3510T>A | S1170R 2D AIThe SynGAP1 missense variant S1170R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of individual predictors lean toward pathogenicity, with the SGM‑Consensus providing a counter‑signal; the evidence is therefore inconclusive. The variant is most likely pathogenic according to the prevailing predictions, and this does not contradict 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 | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.452 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3510T>G | S1170R 2D AIThe SynGAP1 missense variant S1170R 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, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, whereas the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional predictors lean toward pathogenicity, and the most accurate tools also favor a pathogenic classification, with no conflict from ClinVar or gnomAD data. Thus, the variant is most likely pathogenic based on current predictions, 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 Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.452 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.1024T>C | Y342H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y342H is reported in gnomAD (ID 6‑33437929‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Five tools predict pathogenicity versus three predicting benign, with the remaining five (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) yielding uncertain or inconclusive results. High‑accuracy assessments further support a deleterious effect: 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) is uncertain. Overall, the preponderance of evidence indicates that Y342H is most likely pathogenic, and 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 | C2 | 0.366687 | Structured | 0.408200 | Uncertain | 0.866 | 0.487 | 0.250 | 6-33437929-T-C | 1 | 6.20e-7 | -6.459 | Likely Benign | 0.944 | Likely Pathogenic | Ambiguous | 1.63 | Ambiguous | 0.1 | 1.33 | Ambiguous | 1.48 | Ambiguous | 0.73 | Ambiguous | 0.453 | Likely Benign | -3.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.72 | Pathogenic | 0.06 | Tolerated | 3.37 | 25 | 0.2491 | 0.0862 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||
| c.1156G>A | G386R 2D 3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G386R 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 impact are FoldX, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default, while Rosetta is uncertain. High‑accuracy methods give a benign call from AlphaMissense‑Optimized, a pathogenic result from Foldetta, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Overall, the evidence is mixed; the variant is most likely benign, and this assessment does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | -9.024 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 3.62 | Destabilizing | 2.9 | 1.07 | Ambiguous | 2.35 | Destabilizing | 0.29 | Likely Benign | 0.453 | Likely Benign | -0.82 | Neutral | 0.753 | Possibly Damaging | 0.220 | Benign | 4.03 | Benign | 0.01 | Affected | 0.1329 | 0.4032 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1156G>C | G386R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G386R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise FoldX, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and Foldetta; Rosetta 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 balance of evidence favors a pathogenic classification. 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. | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | -9.024 | Likely Pathogenic | 0.709 | Likely Pathogenic | Likely Benign | 3.62 | Destabilizing | 2.9 | 1.07 | Ambiguous | 2.35 | Destabilizing | 0.29 | Likely Benign | 0.453 | Likely Benign | -0.82 | Neutral | 0.753 | Possibly Damaging | 0.220 | Benign | 4.03 | Benign | 0.01 | Affected | 0.1329 | 0.4032 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.3386T>A | L1129Q 2D AIThe SynGAP1 missense variant L1129Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to 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 | 0.903857 | Disordered | 0.876543 | Binding | 0.339 | 0.909 | 0.875 | -3.684 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.453 | Likely Benign | -1.63 | Neutral | 0.846 | Possibly Damaging | 0.525 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.1278 | 0.1436 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3614T>A | L1205Q 2D AIThe SynGAP1 missense variant L1205Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus agrees. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence 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 | Coiled-coil | 0.595080 | Disordered | 0.552471 | Binding | 0.880 | 0.576 | 0.375 | -14.466 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.453 | Likely Benign | -5.02 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.46 | Pathogenic | 0.00 | Affected | 0.1032 | 0.0558 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| 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.703T>A | S235T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235T 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, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, 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 a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or folding result is missing or inconclusive. Based on the overall consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -9.422 | Likely Pathogenic | 0.451 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.0 | -0.54 | Ambiguous | 0.13 | Likely Benign | 0.21 | Likely Benign | 0.453 | Likely Benign | -2.02 | Neutral | 0.057 | Benign | 0.020 | Benign | 5.75 | Benign | 0.13 | Tolerated | 0.1674 | 0.6337 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.787G>C | V263L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive are Rosetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -6.599 | Likely Benign | 0.275 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.40 | Likely Benign | 0.66 | Ambiguous | 0.453 | Likely Benign | -1.26 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.85 | Benign | 0.18 | Tolerated | 0.0759 | 0.3950 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.787G>T | V263L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive are Rosetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -6.599 | Likely Benign | 0.275 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.40 | Likely Benign | 0.66 | Ambiguous | 0.453 | Likely Benign | -1.26 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.85 | Benign | 0.18 | Tolerated | 0.0759 | 0.3950 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.811G>T | A271S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of 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 | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | -9.552 | Likely Pathogenic | 0.629 | Likely Pathogenic | Likely Benign | 0.19 | Likely Benign | 0.1 | 1.47 | Ambiguous | 0.83 | Ambiguous | 1.14 | Destabilizing | 0.453 | Likely Benign | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.64 | Pathogenic | 0.03 | Affected | 0.2260 | 0.3312 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.1283A>G | Y428C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y428C is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus result as “Likely Pathogenic,” Foldetta predicts a destabilizing, pathogenic effect, while AlphaMissense‑Optimized is uncertain. No prediction or stability result is missing; the only inconclusive outcome is the AlphaMissense‑Optimized score. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -11.312 | Likely Pathogenic | 0.852 | Likely Pathogenic | Ambiguous | 2.82 | Destabilizing | 0.0 | 2.99 | Destabilizing | 2.91 | Destabilizing | 2.02 | Destabilizing | 0.454 | Likely Benign | -8.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3322 | 0.2220 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| 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.2039A>T | E680V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E680V missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, premPS, and Foldetta. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and Rosetta is inconclusive. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, more tools (seven) predict pathogenicity than benign (five), and the high‑accuracy consensus leans toward pathogenic. 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 | 0.209395 | Structured | 0.136843 | Uncertain | 0.636 | 0.320 | 0.000 | -12.051 | Likely Pathogenic | 0.936 | Likely Pathogenic | Ambiguous | 0.46 | Likely Benign | 0.3 | -1.08 | Ambiguous | -0.31 | Likely Benign | 0.18 | Likely Benign | 0.454 | Likely Benign | -6.21 | Deleterious | 0.988 | Probably Damaging | 0.606 | Possibly Damaging | 3.47 | Benign | 0.01 | Affected | 0.1091 | 0.7518 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2788C>A | P930T 2D AIThe SynGAP1 missense variant P930T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL classifies it as benign, whereas the remaining 11 predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all indicate pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts a pathogenic change, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability analysis is available. Overall, the consensus of the majority of tools supports a pathogenic classification, and this is consistent with the absence of any 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 | 0.538167 | Disordered | 0.988036 | Binding | 0.304 | 0.855 | 0.375 | -9.558 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.454 | Likely Benign | -5.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.67 | Pathogenic | 0.00 | Affected | 0.1666 | 0.5593 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3436C>A | P1146T 2D AIThe SynGAP1 missense variant P1146T 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, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus call of “Likely Benign.” In contrast, PROVEAN, polyPhen‑2 HumDiv, and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are not available. Overall, the majority of evidence points to a benign effect for P1146T, and 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. | Likely Benign | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | -3.494 | Likely Benign | 0.272 | Likely Benign | Likely Benign | 0.454 | Likely Benign | -4.11 | Deleterious | 0.573 | Possibly Damaging | 0.334 | Benign | 5.51 | Benign | 0.00 | Affected | 0.1478 | 0.5789 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3587A>T | K1196M 2D AIThe SynGAP1 missense variant K1196M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict a pathogenic impact; ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as benign, and Foldetta’s protein‑folding stability result is unavailable. Overall, the majority of conventional tools (four pathogenic vs. three benign) lean toward a pathogenic classification, while the high‑accuracy consensus suggests benign. Based on the aggregate predictions, the variant is most likely pathogenic, and this assessment does not contradict ClinVar, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -7.443 | In-Between | 0.852 | Likely Pathogenic | Ambiguous | 0.454 | Likely Benign | -2.33 | Neutral | 1.000 | Probably Damaging | 0.969 | Probably Damaging | 5.32 | Benign | 0.01 | Affected | 0.0966 | 0.2785 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3659A>G | E1220G 2D AIThe SynGAP1 missense variant E1220G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign change, whereas all other evaluated algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence indicates that E1220G is most likely pathogenic, 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 | Coiled-coil | 0.703578 | Disordered | 0.444845 | Uncertain | 0.881 | 0.551 | 0.375 | -12.121 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.454 | Likely Benign | -6.05 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.61 | Pathogenic | 0.00 | Affected | 0.2791 | 0.4030 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.946A>T | N316Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316Y 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, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign impact. 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 classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -11.226 | Likely Pathogenic | 0.767 | Likely Pathogenic | Likely Benign | 0.53 | Ambiguous | 0.5 | -0.09 | Likely Benign | 0.22 | Likely Benign | 0.50 | Likely Benign | 0.454 | Likely Benign | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.81 | Pathogenic | 0.01 | Affected | 0.0574 | 0.6971 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1063G>T | G355W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G355W is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and premPS, and pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus (derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -12.316 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 1.16 | Ambiguous | 0.5 | 0.88 | Ambiguous | 1.02 | Ambiguous | 0.18 | Likely Benign | 0.455 | Likely Benign | -6.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.73 | Pathogenic | 0.00 | Affected | 0.0796 | 0.4360 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||
| c.1190G>A | C397Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397Y 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, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the combined Foldetta method. Uncertain results come from AlphaMissense‑Default and ESM1b. 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, the majority of tools and the high‑accuracy consensus lean toward a benign interpretation, and this does not contradict any ClinVar classification (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | -7.213 | In-Between | 0.397 | Ambiguous | Likely Benign | 2.01 | Destabilizing | 2.3 | 8.64 | Destabilizing | 5.33 | Destabilizing | 0.12 | Likely Benign | 0.455 | Likely Benign | -1.82 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.64 | Benign | 0.07 | Tolerated | 0.1299 | 0.5084 | 0 | -2 | -3.8 | 60.04 | ||||||||||||||||||||||||||||||
| c.1450T>G | F484V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F484V 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 and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates 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 any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.182256 | Structured | 0.403079 | Uncertain | 0.798 | 0.245 | 0.125 | -15.492 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.08 | Destabilizing | 0.1 | 6.07 | Destabilizing | 6.08 | Destabilizing | 1.28 | Destabilizing | 0.455 | Likely Benign | -6.70 | Deleterious | 0.859 | Possibly Damaging | 0.526 | Possibly Damaging | 2.75 | Benign | 0.00 | Affected | 0.1696 | 0.1902 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| 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.3362G>T | S1121I 2D AIThe SynGAP1 missense variant S1121I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus also as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.215 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.455 | Likely Benign | -0.96 | Neutral | 0.875 | Possibly Damaging | 0.559 | Possibly Damaging | 5.44 | Benign | 0.00 | Affected | 0.1504 | 0.4776 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.3503T>A | I1168N 2D AIThe SynGAP1 missense variant I1168N 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, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) which labels the variant as Likely Benign. In contrast, tools that predict a pathogenic effect are PolyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the evidence is split evenly between benign and pathogenic predictions, with no consensus from the most accurate methods. Consequently, the variant’s pathogenicity is uncertain and does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.642678 | Disordered | 0.763262 | Binding | 0.423 | 0.796 | 0.500 | -4.269 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.455 | Likely Benign | -1.79 | Neutral | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.53 | Benign | 0.01 | Affected | 0.0943 | 0.0969 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||||||||||||
| c.3518T>G | I1173S 2D AIThe SynGAP1 missense variant I1173S 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, ESM1b, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for I1173S, 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 | Coiled-coil | 0.501700 | Disordered | 0.653145 | Binding | 0.521 | 0.756 | 0.375 | -2.416 | Likely Benign | 0.557 | Ambiguous | Likely Benign | 0.455 | Likely Benign | -1.18 | Neutral | 0.625 | Possibly Damaging | 0.265 | Benign | 5.45 | Benign | 0.02 | Affected | 0.2796 | 0.0512 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.661G>C | E221Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools predict a pathogenic outcome: ESM1b and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign), and Foldetta predicts a benign effect. Overall, the majority of evidence (10 benign vs 2 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -8.243 | Likely Pathogenic | 0.825 | Likely Pathogenic | Ambiguous | -0.26 | Likely Benign | 0.1 | -0.33 | Likely Benign | -0.30 | Likely Benign | 0.12 | Likely Benign | 0.455 | Likely Benign | -1.64 | Neutral | 0.028 | Benign | 0.015 | Benign | 6.13 | Benign | 0.23 | Tolerated | 0.1207 | 0.7690 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.1150G>T | G384C 2D AIThe SynGAP1 missense variant G384C 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic; and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split and is treated as unavailable. Overall, the majority of predictions (seven pathogenic vs. five benign) and the pathogenic Foldetta result indicate that the variant is most likely pathogenic, with no contradiction to ClinVar status because the variant is not yet classified there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | -8.363 | Likely Pathogenic | 0.135 | Likely Benign | Likely Benign | 2.41 | Destabilizing | 2.0 | 5.50 | Destabilizing | 3.96 | Destabilizing | 0.17 | Likely Benign | 0.456 | Likely Benign | -1.07 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1530 | 0.4240 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1166C>T | S389L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389L is catalogued in gnomAD (6‑33438071‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, and the SGM‑Consensus score (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments are consistent with 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) predicts Benign. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.703578 | Disordered | 0.417444 | Uncertain | 0.306 | 0.803 | 0.875 | 6-33438071-C-T | 7 | 4.40e-6 | -6.040 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.04 | Likely Benign | 0.1 | 0.69 | Ambiguous | 0.37 | Likely Benign | -0.23 | Likely Benign | 0.456 | Likely Benign | -0.75 | Neutral | 0.462 | Possibly Damaging | 0.693 | Possibly Damaging | 5.05 | Benign | 0.01 | Affected | 4.32 | 8 | 0.1844 | 0.5871 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||
| c.1700A>G | E567G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E567G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact include REVEL, SIFT, and FATHMM, whereas those that agree on pathogenic impact include AlphaMissense‑Default, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and Foldetta. Predictions that are inconclusive are FoldX, 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 (combining FoldX‑MD and Rosetta outputs) as pathogenic. Taken together, 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 | 0.021816 | Structured | 0.051008 | Uncertain | 0.916 | 0.234 | 0.000 | -13.402 | Likely Pathogenic | 0.912 | Likely Pathogenic | Ambiguous | 1.47 | Ambiguous | 0.0 | 3.48 | Destabilizing | 2.48 | Destabilizing | 0.75 | Ambiguous | 0.456 | Likely Benign | -6.67 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.40 | Benign | 0.07 | Tolerated | 0.2586 | 0.4715 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.3143G>C | G1048A 2D AISynGAP1 missense variant G1048A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that G1048A is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -4.821 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.456 | Likely Benign | -0.14 | Neutral | 0.573 | Possibly Damaging | 0.358 | Benign | 2.57 | Benign | 0.64 | Tolerated | 0.3301 | 0.5138 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3412T>C | S1138P 2D AIThe SynGAP1 missense variant S1138P 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, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | -5.023 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.456 | Likely Benign | -1.21 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.41 | Benign | 0.10 | Tolerated | 0.2297 | 0.5856 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.931C>T | H311Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311Y 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, ESM1b, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools with uncertain or inconclusive results—Rosetta, Foldetta, and AlphaMissense‑Default—are treated as unavailable for pathogenicity assessment. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the predictions are split, with five tools favoring benign, five favoring pathogenic, and three inconclusive. Based on the available evidence, the variant is most likely pathogenic, and 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 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -4.513 | Likely Benign | 0.342 | Ambiguous | Likely Benign | -0.06 | Likely Benign | 0.2 | -1.58 | Ambiguous | -0.82 | Ambiguous | 0.18 | Likely Benign | 0.456 | Likely Benign | -3.80 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.86 | Pathogenic | 0.02 | Affected | 0.0965 | 0.4180 | 0 | 2 | 1.9 | 26.03 | ||||||||||||||||||||||||||||||
| c.1163G>C | G388A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388A 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 stability outputs) as Pathogenic. Overall, the predictions are mixed, but the two most reliable tools (AlphaMissense‑Optimized and SGM‑Consensus) favor a benign interpretation, while Foldetta suggests instability. Based on the available predictions, 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 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | -6.577 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 2.55 | Destabilizing | 1.9 | 3.57 | Destabilizing | 3.06 | Destabilizing | -0.04 | Likely Benign | 0.457 | Likely Benign | -0.57 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.05 | Affected | 0.3969 | 0.4837 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2771C>A | P924H 2D AIThe SynGAP1 missense variant P924H 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 REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of computational evidence indicates that P924H 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 | 0.521092 | Disordered | 0.971858 | Binding | 0.293 | 0.846 | 0.250 | -6.236 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.457 | Likely Benign | -5.87 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.65 | Pathogenic | 0.00 | Affected | 0.1317 | 0.3281 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3154G>T | G1052W 2D AIThe SynGAP1 missense variant G1052W 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, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 Benign | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -11.322 | Likely Pathogenic | 0.309 | Likely Benign | Likely Benign | 0.457 | Likely Benign | -0.90 | Neutral | 0.997 | Probably Damaging | 0.946 | Probably Damaging | 3.90 | Benign | 0.02 | Affected | 0.0872 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3767A>G | D1256G 2D AIThe SynGAP1 missense variant D1256G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the benign‑predicting REVEL score, and a consensus of pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenicity. Foldetta results are unavailable. Overall, the preponderance of evidence from both general and high‑accuracy tools points to a pathogenic effect for D1256G. This conclusion is consistent with the absence 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 | Coiled-coil | 0.549308 | Disordered | 0.445789 | Uncertain | 0.876 | 0.571 | 0.625 | -11.341 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.457 | Likely Benign | -5.45 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 0.2886 | 0.5040 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| c.874G>A | A292T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all 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) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, 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 | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -11.039 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.7 | 3.42 | Destabilizing | 2.79 | Destabilizing | 1.08 | Destabilizing | 0.457 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.68 | Pathogenic | 0.01 | Affected | 0.1691 | 0.7377 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1015A>C | K339Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. 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. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evaluated tools (8 pathogenic vs. 4 benign) indicate a pathogenic effect. 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 | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -10.952 | Likely Pathogenic | 0.863 | Likely Pathogenic | Ambiguous | 0.06 | Likely Benign | 0.0 | -0.50 | Ambiguous | -0.22 | Likely Benign | -0.02 | Likely Benign | 0.458 | Likely Benign | -3.06 | Deleterious | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 1.90 | Pathogenic | 0.04 | Affected | 0.4041 | 0.1012 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1157G>T | G386V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G386V is reported in gnomAD (6-33438062‑G‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show 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 classification, 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 Benign | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | 6-33438062-G-T | -6.405 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 4.88 | Destabilizing | 3.0 | 5.09 | Destabilizing | 4.99 | Destabilizing | -0.17 | Likely Benign | 0.458 | Likely Benign | -0.64 | Neutral | 0.985 | Probably Damaging | 0.720 | Possibly Damaging | 3.91 | Benign | 0.01 | Affected | 4.32 | 3 | 0.1685 | 0.4189 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||
| c.1282T>C | Y428H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y428H is not reported in ClinVar but is present in gnomAD (ID 6‑33438187‑T‑C). Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM Consensus score (Likely Pathogenic) all suggest a deleterious impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Consequently, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | 6-33438187-T-C | 1 | 6.19e-7 | -8.566 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 3.18 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.69 | Destabilizing | 1.80 | Destabilizing | 0.458 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 3.38 | 25 | 0.2685 | 0.0711 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||
| c.1556A>G | E519G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E519G missense variant is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and premPS. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized is uncertain; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; Foldetta is uncertain. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) lean toward a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.078022 | Structured | 0.104514 | Uncertain | 0.899 | 0.328 | 0.000 | -10.835 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.22 | Likely Benign | 0.1 | 0.92 | Ambiguous | 0.57 | Ambiguous | 0.22 | Likely Benign | 0.458 | Likely Benign | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0.2729 | 0.3471 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1880C>G | A627G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A627G 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. Tools that agree on a pathogenic effect comprise SGM‑Consensus, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta remains uncertain. Overall, the majority of evidence points to 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. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -11.716 | Likely Pathogenic | 0.640 | Likely Pathogenic | Likely Benign | 1.38 | Ambiguous | 0.1 | 2.07 | Destabilizing | 1.73 | Ambiguous | 1.25 | Destabilizing | 0.458 | Likely Benign | -3.96 | Deleterious | 0.997 | Probably Damaging | 0.876 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1921 | 0.2990 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.2134G>C | G712R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G712R 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—PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, SIFT, ESM1b, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta, and the SGM Consensus—classify it as pathogenic. Two tools, FoldX and premPS, return uncertain results. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta each predict a deleterious effect. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -11.776 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 1.75 | Ambiguous | 0.0 | 4.68 | Destabilizing | 3.22 | Destabilizing | 0.82 | Ambiguous | 0.458 | Likely Benign | -6.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | 0.1229 | 0.4482 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.2777C>T | S926F 2D AIThe SynGAP1 missense variant S926F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S926F is most likely pathogenic, 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 Pathogenic | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -6.157 | Likely Benign | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.458 | Likely Benign | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.50 | Pathogenic | 0.00 | Affected | 0.0585 | 0.5220 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.682A>T | T228S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228S 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, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign stability change. Taken together, the overwhelming majority of evidence indicates a benign impact for T228S. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -2.028 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.48 | Likely Benign | 0.05 | Likely Benign | 0.458 | Likely Benign | -0.50 | Neutral | 0.734 | Possibly Damaging | 0.138 | Benign | 5.65 | Benign | 1.00 | Tolerated | 0.3395 | 0.5107 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.995A>C | D332A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332A 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 Rosetta, while the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect. This conclusion 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 | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -12.290 | Likely Pathogenic | 0.876 | Likely Pathogenic | Ambiguous | 1.19 | Ambiguous | 0.2 | 0.32 | Likely Benign | 0.76 | Ambiguous | 0.54 | Ambiguous | 0.458 | Likely Benign | -6.45 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.24 | Pathogenic | 0.02 | Affected | 0.2998 | 0.4176 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1022G>T | G341V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G341V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, polyPhen‑2 HumVar, and the SGM‑Consensus score (derived from a majority of benign calls among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No evidence from FoldX or premPS is available. Overall, the majority of predictions support a benign classification, and this is consistent with the lack of ClinVar annotation. Therefore, the variant is most likely benign and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.431164 | Uncertain | 0.745 | 0.479 | 0.250 | -5.371 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.86 | Ambiguous | 0.3 | -2.24 | Stabilizing | -0.69 | Ambiguous | -0.50 | Ambiguous | 0.459 | Likely Benign | -2.29 | Neutral | 0.801 | Possibly Damaging | 0.192 | Benign | 0.42 | Pathogenic | 0.05 | Affected | 0.1019 | 0.3649 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1160G>A | G387D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G387D is reported in gnomAD (6‑33438065‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, SIFT, ESM1b, FATHMM, 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, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With two of the three high‑accuracy methods indicating pathogenicity and a majority of general predictors leaning toward pathogenic, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | 6-33438065-G-A | 2 | 1.24e-6 | -8.625 | Likely Pathogenic | 0.612 | Likely Pathogenic | Likely Benign | 3.57 | Destabilizing | 2.3 | 3.22 | Destabilizing | 3.40 | Destabilizing | 0.39 | Likely Benign | 0.459 | Likely Benign | -0.37 | Neutral | 0.069 | Benign | 0.041 | Benign | 1.32 | Pathogenic | 0.02 | Affected | 4.32 | 3 | 0.2145 | 0.2035 | -1 | 1 | -3.1 | 58.04 | ||||||||||||||||||||||||
| 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.1460A>G | N487S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N487S 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 (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is inconclusive, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is also inconclusive. Overall, the preponderance of evidence from multiple in silico predictors and the SGM Consensus indicates that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -10.297 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 1.42 | Ambiguous | 0.0 | 1.49 | Ambiguous | 1.46 | Ambiguous | 0.65 | Ambiguous | 0.459 | Likely Benign | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 2.74 | Benign | 0.01 | Affected | 0.3065 | 0.3656 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.1769G>C | S590T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590T 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, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and ESM1b. Two tools (premPS and AlphaMissense‑Default) return 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 (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 lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -12.472 | Likely Pathogenic | 0.458 | Ambiguous | Likely Benign | 0.23 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.33 | Likely Benign | 0.64 | Ambiguous | 0.459 | Likely Benign | -2.89 | Deleterious | 0.183 | Benign | 0.050 | Benign | 3.15 | Benign | 0.08 | Tolerated | 0.1420 | 0.5723 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.2108T>G | L703R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L703R 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) all classify the change as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. The preponderance of pathogenic predictions, together with the high‑accuracy tools’ positive results, suggests that L703R is most likely pathogenic. 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 | 0.144935 | Structured | 0.388282 | Uncertain | 0.929 | 0.353 | 0.000 | -13.244 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 2.85 | Destabilizing | 0.0 | 3.74 | Destabilizing | 3.30 | Destabilizing | 1.79 | Destabilizing | 0.459 | Likely Benign | -4.92 | Deleterious | 0.994 | Probably Damaging | 0.806 | Possibly Damaging | 3.13 | Benign | 0.00 | Affected | 0.1223 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.2830G>C | G944R 2D AIThe SynGAP1 missense variant G944R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G944R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -6.577 | Likely Benign | 0.359 | Ambiguous | Likely Benign | 0.459 | Likely Benign | -1.82 | Neutral | 0.639 | Possibly Damaging | 0.299 | Benign | 3.73 | Benign | 0.00 | Affected | 0.1030 | 0.4733 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3527A>G | E1176G 2D AIThe SynGAP1 missense variant E1176G 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, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic impact. 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 results are unavailable. Overall, the balance of evidence—five benign predictions versus three pathogenic, a consensus leaning benign, and no conflicting ClinVar annotation—suggests that E1176G is most likely benign. 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 | Coiled-coil | 0.538167 | Disordered | 0.572075 | Binding | 0.525 | 0.715 | 0.250 | -4.531 | Likely Benign | 0.838 | Likely Pathogenic | Ambiguous | 0.459 | Likely Benign | -2.14 | Neutral | 0.995 | Probably Damaging | 0.963 | Probably Damaging | 5.48 | Benign | 0.08 | Tolerated | 0.2668 | 0.5414 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||
| c.3776T>A | I1259N 2D AIThe SynGAP1 missense variant I1259N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: 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) all indicate likely pathogenicity. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also reports a likely pathogenic classification. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect for I1259N. 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 | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -10.979 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.459 | Likely Benign | -3.55 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.0799 | 0.0340 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.649G>C | E217Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E217Q is reported in gnomAD (ID 6‑33435291‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With six benign versus three pathogenic calls and a benign consensus from the high‑accuracy panel, the variant is most likely benign. This conclusion does not contradict ClinVar, which contains no classification for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | 6-33435291-G-C | 1 | 6.20e-7 | -6.810 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.2 | 1.61 | Ambiguous | 0.93 | Ambiguous | 0.67 | Ambiguous | 0.459 | Likely Benign | -1.89 | Neutral | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.83 | Benign | 0.14 | Tolerated | 3.41 | 13 | 0.1474 | 0.8473 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||
| c.1073T>G | F358C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F358C is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls arise from Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is inconclusive, Foldetta is inconclusive, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenic. Because the majority of available predictions favor a damaging effect, the variant is most likely pathogenic, 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. | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -7.966 | In-Between | 0.927 | Likely Pathogenic | Ambiguous | 1.68 | Ambiguous | 0.1 | 2.19 | Destabilizing | 1.94 | Ambiguous | 1.18 | Destabilizing | 0.460 | Likely Benign | -6.36 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 4.02 | Benign | 0.06 | Tolerated | 0.2364 | 0.1800 | -4 | -2 | -0.3 | -44.04 | ||||||||||||||||||||||||||||||
| c.1151G>T | G384V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G384V is catalogued in gnomAD (ID 6‑33438056‑G‑T) but has no entry in ClinVar. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a pathogenic effect on protein stability. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | 6-33438056-G-T | -6.968 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 3.69 | Destabilizing | 0.4 | 6.77 | Destabilizing | 5.23 | Destabilizing | -0.11 | Likely Benign | 0.460 | Likely Benign | -1.01 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 2 | 0.1599 | 0.3708 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||
| c.1165T>C | S389P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389P is listed in gnomAD (variant ID 6‑33438070‑T‑C) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.703578 | Disordered | 0.417444 | Uncertain | 0.306 | 0.803 | 0.875 | 6-33438070-T-C | -5.286 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 1.85 | Ambiguous | 2.0 | -0.99 | Ambiguous | 0.43 | Likely Benign | 0.16 | Likely Benign | 0.460 | Likely Benign | -0.44 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 5.05 | Benign | 0.01 | Affected | 4.32 | 8 | 0.3098 | 0.7002 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||
| c.2153T>A | L718H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718H is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools cluster into two groups: the single benign predictor REVEL, and a consensus of pathogenic predictions from FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are inconclusive or missing. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.298791 | Structured | 0.438417 | Uncertain | 0.966 | 0.385 | 0.000 | -14.923 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.84 | Destabilizing | 0.1 | 2.68 | Destabilizing | 3.26 | Destabilizing | 2.69 | Destabilizing | 0.460 | Likely Benign | -6.64 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.1020 | 0.0526 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.3152G>T | G1051V 2D AIThe SynGAP1 missense variant G1051V is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33443704‑G‑T). Prediction tools that agree on a benign effect include REVEL, 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 show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for G1051V, 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. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | 6-33443704-G-T | 1 | 6.20e-7 | -7.098 | In-Between | 0.102 | Likely Benign | Likely Benign | 0.460 | Likely Benign | -0.62 | Neutral | 0.245 | Benign | 0.096 | Benign | -0.74 | Pathogenic | 0.17 | Tolerated | 3.77 | 5 | 0.1274 | 0.3680 | -3 | -1 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||
| c.844T>A | C282S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the majority of other in‑silico predictors (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, and Foldetta) return 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 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 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | Uncertain | 1 | -11.846 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.1 | 1.23 | Ambiguous | 1.39 | Ambiguous | 1.62 | Destabilizing | 0.460 | Likely Benign | -9.19 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.64 | Pathogenic | 0.03 | Affected | 3.39 | 18 | 0.5009 | 0.1286 | Weaken | 0 | -1 | -3.3 | -16.06 | 233.2 | 14.8 | -0.1 | 0.0 | -0.2 | 0.3 | X | Potentially Benign | The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), packs against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the hydroxyl-containing side chain of Ser282 is more hydrophilic and, hence, not as favorable as Cys282 for this hydrophobic niche. Due to this polarity difference, the residue swap could potentially weaken the hydrophobic packing of the C2 domain during the folding process.Moreover, because the C2 domain interacts with the membrane, there could also be a negative effect on the stability of the SynGAP-membrane association. However, no large-scale structural changes were observed during the variant simulations. The hydroxyl group of Ser282 forms a hydrogen bond with the backbone carbonyl group of His326 in another β strand (res. Ala322-Arg329), which competes directly with the backbone amide group of Glu283 within the secondary structure element. | |||||||||||||||
| c.862G>C | D288H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D288H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, and premPS. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling the variant as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect on protein folding stability. Overall, the majority of tools (7/12) predict pathogenicity, and the high‑accuracy consensus leans toward pathogenic, with no conflict with ClinVar status. 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 | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -12.589 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.1 | 0.36 | Likely Benign | 0.22 | Likely Benign | -0.02 | Likely Benign | 0.460 | Likely Benign | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.65 | Pathogenic | 0.01 | Affected | 0.1639 | 0.6254 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.1238C>T | P413L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P413L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, premPS, and FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.735 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.61 | Destabilizing | 0.4 | 1.34 | Ambiguous | 1.98 | Ambiguous | 0.30 | Likely Benign | 0.461 | Likely Benign | -9.21 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.2056 | 0.5614 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| 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.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.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.3125A>C | Q1042P 2D AIThe SynGAP1 missense variant Q1042P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv 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 further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are not available. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -2.085 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.461 | Likely Benign | -0.73 | Neutral | 0.586 | Possibly Damaging | 0.223 | Benign | 5.42 | Benign | 0.31 | Tolerated | 0.2336 | 0.5762 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| 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.814C>T | R272W 2D AISynGAP1 missense variant R272W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict deleterious effects, while the consensus SGM tool (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely pathogenic outcome. Benign predictions are limited to REVEL, Rosetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the balance of evidence favors a pathogenic impact for R272W, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.071867 | Structured | 0.425620 | Uncertain | 0.925 | 0.215 | 0.125 | -12.145 | Likely Pathogenic | 0.863 | Likely Pathogenic | Ambiguous | 2.98 | Destabilizing | 1.6 | 0.12 | Likely Benign | 1.55 | Ambiguous | 0.19 | Likely Benign | 0.461 | Likely Benign | -5.49 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.72 | Pathogenic | 0.00 | Affected | 0.1460 | 0.3643 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||
| c.1171G>A | G391S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G391S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, 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, FATHMM, and FoldX. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as likely benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact for G391S, 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 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -5.531 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 2.14 | Destabilizing | 0.6 | 1.01 | Ambiguous | 1.58 | Ambiguous | 0.06 | Likely Benign | 0.462 | Likely Benign | -0.54 | Neutral | 0.978 | Probably Damaging | 0.777 | Possibly Damaging | 1.33 | Pathogenic | 0.35 | Tolerated | 0.2820 | 0.5097 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| 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.2345A>T | D782V 2D AIThe SynGAP1 missense variant D782V 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 REVEL, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which reports “Likely Pathogenic”). The high‑accuracy AlphaMissense‑Optimized tool yields an uncertain result, and the Foldetta stability assessment is unavailable. Overall, the consensus of the available predictions strongly favors a pathogenic effect for D782V. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -8.250 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 0.462 | Likely Benign | -3.59 | Deleterious | 0.999 | Probably Damaging | 0.979 | Probably Damaging | 1.92 | Pathogenic | 0.00 | Affected | 0.0803 | 0.6477 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3778A>G | K1260E 2D AIThe SynGAP1 missense variant K1260E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus remains pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions point to a pathogenic effect, and there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.509769 | Disordered | 0.625808 | Binding | 0.890 | 0.575 | 0.250 | -10.913 | Likely Pathogenic | 0.846 | Likely Pathogenic | Ambiguous | 0.462 | Likely Benign | -3.06 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.38 | Pathogenic | 0.00 | Affected | 0.3129 | 0.0877 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.1474A>C | K492Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -14.685 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.34 | Likely Benign | 0.0 | 0.93 | Ambiguous | 0.64 | Ambiguous | 1.13 | Destabilizing | 0.463 | Likely Benign | -3.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.98 | Benign | 0.02 | Affected | 0.3534 | 0.0830 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| 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.3128G>C | R1043T 2D AIThe SynGAP1 missense variant R1043T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the 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 | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -3.928 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.463 | Likely Benign | -1.77 | Neutral | 0.001 | Benign | 0.003 | Benign | 5.39 | Benign | 0.00 | Affected | 0.1975 | 0.5513 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.3710A>C | Y1237S 2D AIThe SynGAP1 missense variant Y1237S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic. The SGM‑Consensus, a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, therefore also predicts pathogenicity. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) is pathogenic; Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the lack of any benign consensus, the variant is most likely pathogenic, 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 Pathogenic | Coiled-coil | 0.653063 | Disordered | 0.563444 | Binding | 0.842 | 0.535 | 0.125 | -10.349 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.463 | Likely Benign | -7.21 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.45 | Pathogenic | 0.00 | Affected | 0.5127 | 0.0891 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||
| c.3785T>A | I1262N 2D AIThe SynGAP1 missense variant I1262N is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools largely agree on a deleterious effect: REVEL predicts a benign outcome, whereas all other evaluated algorithms—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, 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 reports a likely pathogenic status. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the preponderance of computational evidence indicates that I1262N 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 | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -14.512 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.463 | Likely Benign | -5.81 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.00 | Affected | 0.0940 | 0.0340 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| 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.1058T>C | L353P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L353P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL predicts benign, whereas FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict pathogenic. Two tools report uncertainty: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Overall, the majority of evidence points to a pathogenic impact, which is consistent with the ClinVar designation of uncertain significance but leans toward pathogenicity rather than benign. Thus, the variant is most likely pathogenic, and this prediction does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | Uncertain | 1 | -7.913 | In-Between | 0.936 | Likely Pathogenic | Ambiguous | 4.63 | Destabilizing | 0.1 | 10.19 | Destabilizing | 7.41 | Destabilizing | 2.17 | Destabilizing | 0.464 | Likely Benign | -3.70 | Deleterious | 0.947 | Possibly Damaging | 0.454 | Possibly Damaging | 1.29 | Pathogenic | 0.02 | Affected | 3.37 | 25 | 0.3582 | 0.1645 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| 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.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.1980G>A | M660I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M660I 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, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and the protein‑folding stability method Foldetta returns an uncertain result. Stability predictions from FoldX, Rosetta, and premPS are also inconclusive. Overall, the majority of evidence points to a pathogenic effect for M660I. 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 | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -11.150 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.93 | Ambiguous | 0.95 | Ambiguous | 0.464 | Likely Benign | -3.99 | Deleterious | 0.887 | Possibly Damaging | 0.289 | Benign | 3.52 | Benign | 0.04 | Affected | 0.1170 | 0.2878 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1980G>C | M660I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M660I (GAP domain) is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumVar, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other stability predictions are available. Overall, the preponderance of evidence points to a pathogenic effect for M660I. 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 | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -11.150 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.93 | Ambiguous | 0.95 | Ambiguous | 0.464 | Likely Benign | -3.99 | Deleterious | 0.887 | Possibly Damaging | 0.289 | Benign | 3.52 | Benign | 0.04 | Affected | 0.1170 | 0.2878 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.1980G>T | M660I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M660I (GAP domain) is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumVar, and FATHMM. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other stability predictions are available. Overall, the preponderance of evidence points to a pathogenic effect for M660I. 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 | 0.047319 | Structured | 0.134270 | Uncertain | 0.944 | 0.289 | 0.000 | -11.150 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.93 | Ambiguous | 0.95 | Ambiguous | 0.464 | Likely Benign | -3.99 | Deleterious | 0.887 | Possibly Damaging | 0.289 | Benign | 3.52 | Benign | 0.04 | Affected | 0.1170 | 0.2878 | 2 | 1 | 2.6 | -18.03 | |||||||||||||||||||||||||||||
| c.3382G>T | G1128W 2D AIThe SynGAP1 missense variant G1128W is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields an inconclusive result (two benign, two uncertain), and Foldetta data are unavailable. Overall, the balance of evidence favors a benign classification. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -7.341 | In-Between | 0.402 | Ambiguous | Likely Benign | 0.464 | Likely Benign | -1.36 | Neutral | 0.011 | Benign | 0.008 | Benign | 4.36 | Benign | 0.02 | Affected | 0.0796 | 0.4540 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||||||||||||
| c.670A>G | T224A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T224A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33435521‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default. The remaining tools (Rosetta, Foldetta, premPS, ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of 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. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | Uncertain | 3 | 6-33435521-A-G | 2 | 1.24e-6 | -7.379 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.33 | Likely Benign | 0.1 | 1.05 | Ambiguous | 0.69 | Ambiguous | 0.91 | Ambiguous | 0.464 | Likely Benign | -2.96 | Deleterious | 0.243 | Benign | 0.079 | Benign | 5.57 | Benign | 0.57 | Tolerated | 3.41 | 13 | 0.4253 | 0.5053 | 1 | 0 | 2.5 | -30.03 | 169.0 | 41.4 | -0.5 | 1.1 | -0.4 | 0.0 | X | X | Uncertain | The introduced residue Ala224 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr224 side chain in the WT model, the methyl side chain of Ala224 cannot form hydrogen bonds with nearby residues Ser204, Ser226, and Gly227. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and unfolds during the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.1115G>C | G372A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also return uncertain results. Overall, the majority of evidence points to a benign impact for G372A, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -5.163 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 1.52 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.55 | Ambiguous | -0.12 | Likely Benign | 0.465 | Likely Benign | -0.32 | Neutral | 0.000 | Benign | 0.000 | Benign | -0.74 | Pathogenic | 0.03 | Affected | 0.3956 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1753G>A | A585T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A585T is reported in gnomAD (ID 6‑33440805‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, and SIFT, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain 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 balance of evidence favors a pathogenic effect for A585T. This conclusion is not contradicted by ClinVar, which contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.055884 | Uncertain | 0.880 | 0.244 | 0.000 | 6-33440805-G-A | 13 | 8.05e-6 | -10.063 | Likely Pathogenic | 0.876 | Likely Pathogenic | Ambiguous | 1.66 | Ambiguous | 0.2 | 1.97 | Ambiguous | 1.82 | Ambiguous | 0.23 | Likely Benign | 0.465 | Likely Benign | -1.73 | Neutral | 1.000 | Probably Damaging | 0.994 | Probably Damaging | -1.30 | Pathogenic | 0.26 | Tolerated | 3.37 | 35 | 0.1132 | 0.4212 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||
| c.1948A>C | N650H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650H 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 REVEL and FATHMM. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, FoldX, and the SGM‑Consensus (majority vote). Uncertain or inconclusive results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus also indicates likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -14.187 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.14 | Destabilizing | 0.3 | 1.79 | Ambiguous | 1.97 | Ambiguous | 0.55 | Ambiguous | 0.465 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.929 | Probably Damaging | 3.01 | Benign | 0.05 | Affected | 0.1990 | 0.4784 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.3894G>T | Q1298H 2D  AIThe SynGAP1 missense variant Q1298H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign classification, 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -4.109 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.465 | Likely Benign | -1.45 | Neutral | 0.938 | Possibly Damaging | 0.377 | Benign | 2.77 | Benign | 0.03 | Affected | 0.1083 | 0.2605 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| 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.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.1177G>A | G393S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, polyPhen‑2 HumDiv, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. No other tools provide decisive evidence. Overall, the majority of reliable predictors lean toward a benign effect, and this consensus does not conflict with the absence of ClinVar annotation. Therefore, G393S is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -5.207 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 2.43 | Destabilizing | 0.7 | -0.78 | Ambiguous | 0.83 | Ambiguous | 0.24 | Likely Benign | 0.466 | Likely Benign | -1.76 | Neutral | 0.889 | Possibly Damaging | 0.444 | Benign | 1.33 | Pathogenic | 0.07 | Tolerated | 0.3011 | 0.5232 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1749C>G | D583E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D583E 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, and SIFT. Those that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and ESM1b. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign, and AlphaMissense‑Optimized as Uncertain. 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 | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -7.861 | In-Between | 0.851 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.2 | -0.36 | Likely Benign | -0.06 | Likely Benign | -0.20 | Likely Benign | 0.466 | Likely Benign | -3.52 | Deleterious | 0.960 | Probably Damaging | 0.969 | Probably Damaging | -1.18 | Pathogenic | 0.12 | Tolerated | 0.1200 | 0.4037 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2092G>A | E698K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E698K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, 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, SGM‑Consensus as likely pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a benign impact. Because the high‑accuracy predictions are split, the overall evidence is inconclusive, but the majority of tools lean toward pathogenicity. The variant is therefore most likely pathogenic based on the preponderance of 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 | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -8.881 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.23 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.31 | Likely Benign | -0.07 | Likely Benign | 0.466 | Likely Benign | -3.79 | Deleterious | 0.991 | Probably Damaging | 0.951 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.2218 | 0.4383 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.2162T>G | I721S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I721S is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess the variant’s effect fall into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic outcome. 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 predictions are missing or inconclusive. 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 | 0.394753 | Structured | 0.454550 | Uncertain | 0.957 | 0.437 | 0.125 | Uncertain | 1 | -14.032 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.91 | Destabilizing | 0.1 | 3.96 | Destabilizing | 3.94 | Destabilizing | 2.28 | Destabilizing | 0.466 | Likely Benign | -5.26 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.21 | Pathogenic | 0.00 | Affected | 3.50 | 9 | 0.2606 | 0.1110 | -1 | -2 | -5.3 | -26.08 | 203.3 | 49.3 | -0.1 | 0.0 | -1.1 | 0.0 | X | Uncertain | The sec-butyl side chain of Ile721, located on an α-helix (res. Leu714-Arg726), engages in hydrophobic packing with other residues in the hydrophobic inter-helix space, such as Phe420, Tyr417, His693, and Leu717. In the variant simulations, the hydroxyl side chain of Ser721 forms hydrogen bonds with nearby residues, such as Leu717 and His693. Although no major structural changes are observed during the variant simulations, the hydrophilic residue Ser721 could disrupt the hydrophobic packing during folding. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | ||||||||||||||||
| c.623C>T | P208L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P208L has no ClinVar entry and is present in gnomAD (ID 6‑33435265‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, while those that agree on a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are inconclusive are Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall distribution of 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 | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | 6-33435265-C-T | 1 | 6.20e-7 | -10.013 | Likely Pathogenic | 0.889 | Likely Pathogenic | Ambiguous | 2.35 | Destabilizing | 0.5 | 0.04 | Likely Benign | 1.20 | Ambiguous | 0.67 | Ambiguous | 0.466 | Likely Benign | -8.49 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.75 | Benign | 0.01 | Affected | 3.44 | 12 | 0.2219 | 0.6191 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||
| c.812C>T | A271V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, and Foldetta, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and Rosetta. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains inconclusive; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points toward a pathogenic impact, 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 Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | -8.185 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | -0.22 | Likely Benign | 0.2 | 0.78 | Ambiguous | 0.28 | Likely Benign | 0.37 | Likely Benign | 0.466 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.69 | Pathogenic | 0.02 | Affected | 0.0986 | 0.4409 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.844T>C | C282R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282R is listed in ClinVar as Pathogenic (ClinVar ID 635755.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. All other evaluated algorithms predict a pathogenic outcome: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Rosetta’s output is uncertain and is therefore not counted as evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. Based on the overwhelming agreement among these predictions, 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 | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | Pathogenic | 2 | -16.378 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.13 | Destabilizing | 0.6 | 1.58 | Ambiguous | 2.36 | Destabilizing | 1.70 | Destabilizing | 0.466 | Likely Benign | -11.03 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.63 | Pathogenic | 0.00 | Affected | 3.39 | 18 | 0.1696 | 0.1557 | -4 | -3 | -7.0 | 53.05 | 297.4 | -98.2 | -0.1 | 0.1 | 0.5 | 0.0 | X | X | X | Potentially Pathogenic | The thiol-containing side chain of Cys282, located at the beginning of an anti-parallel β sheet strand (res. Arg279-Leu286), is packed against multiple hydrophobic residues (e.g., Ile268, Leu284, Trp308, Leu327). In the variant simulations, the bulky side chain of Arg282 with its positively charged guanidinium group is not suitable for this hydrophobic niche. Consequently, the hydrophobic residues must either make room to accommodate Arg282 or it must escape the hydrophobic C2 domain core.As a result, new hydrogen bonds are formed with the backbone carbonyl groups of the surrounding β sheet residues Ala399, Leu325, and His326, which decreases the unity of the secondary structure elements. Notably, it is likely that the residue swap causes major problems during the C2 domain folding that are not visible in the variant simulations. In fact, even increased lability in the C2 domain could adversely affect the establishment of a stable SynGAP-membrane association. | ||||||||||||||
| c.1749C>A | D583E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D583E 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, and SIFT. Those that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and ESM1b. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign, and AlphaMissense‑Optimized as Uncertain. 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 | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -7.861 | In-Between | 0.851 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.2 | -0.36 | Likely Benign | -0.06 | Likely Benign | -0.20 | Likely Benign | 0.467 | Likely Benign | -3.52 | Deleterious | 0.960 | Probably Damaging | 0.969 | Probably Damaging | -1.18 | Pathogenic | 0.12 | Tolerated | 0.1200 | 0.4037 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1952A>T | E651V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E651V missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools split in their assessment: benign‑predicted scores include REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic‑predicted scores come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and FoldX give uncertain results. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans pathogenic (3 pathogenic vs. 1 benign); Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Overall, the majority of tools (including the high‑accuracy SGM Consensus) suggest a pathogenic impact, whereas Foldetta and several other predictors indicate benign. The variant is most likely pathogenic based on the prevailing 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 | 0.088832 | Structured | 0.365409 | Uncertain | 0.955 | 0.340 | 0.000 | -10.025 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.63 | Ambiguous | 0.1 | 0.25 | Likely Benign | 0.44 | Likely Benign | 0.21 | Likely Benign | 0.467 | Likely Benign | -5.53 | Deleterious | 0.988 | Probably Damaging | 0.734 | Possibly Damaging | 3.27 | Benign | 0.05 | Affected | 0.0824 | 0.6136 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1954T>C | F652L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F652L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and FATHMM, whereas the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all indicate pathogenicity. Stability‑based assessments from FoldX and Rosetta are inconclusive, and Foldetta likewise yields an uncertain result. High‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels the variant as likely pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for F652L. This conclusion is consistent with the absence of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.098513 | Structured | 0.356594 | Uncertain | 0.966 | 0.338 | 0.000 | -9.026 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.1 | 1.88 | Ambiguous | 1.60 | Ambiguous | 1.35 | Destabilizing | 0.467 | Likely Benign | -5.65 | Deleterious | 0.997 | Probably Damaging | 0.619 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1750 | 0.2926 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.3530A>C | E1177A 2D AIThe SynGAP1 missense variant E1177A 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, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome, reflecting the 3:1 benign majority among its constituents. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign effect for E1177A, and this conclusion does not conflict with ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.566503 | Binding | 0.542 | 0.705 | 0.250 | -3.050 | Likely Benign | 0.774 | Likely Pathogenic | Likely Benign | 0.467 | Likely Benign | -2.12 | Neutral | 0.905 | Possibly Damaging | 0.373 | Benign | 5.50 | Benign | 0.03 | Affected | 0.2919 | 0.4369 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||||||
| 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.1942T>C | F648L 2D AISynGAP1 missense variant F648L is listed in ClinVar with an uncertain significance (ClinVar ID 3383902.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas the remaining tools—FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b—consistently predict pathogenicity. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic change. Taken together, the preponderance of evidence points to a pathogenic impact for F648L, which contradicts the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | Uncertain | 1 | -9.296 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.71 | Destabilizing | 0.8 | 2.08 | Destabilizing | 2.40 | Destabilizing | 1.04 | Destabilizing | 0.468 | Likely Benign | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | 3.45 | Benign | 0.08 | Tolerated | 0.1961 | 0.3126 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||
| c.2096T>A | V699E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V699E missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign 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 score) indicate a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy tools’ results, the variant is most likely pathogenic, and this assessment does not contradict 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 | 0.069024 | Structured | 0.432975 | Uncertain | 0.935 | 0.315 | 0.000 | -12.647 | Likely Pathogenic | 0.813 | Likely Pathogenic | Ambiguous | 2.41 | Destabilizing | 0.1 | 2.08 | Destabilizing | 2.25 | Destabilizing | 1.82 | Destabilizing | 0.468 | Likely Benign | -4.56 | Deleterious | 1.000 | Probably Damaging | 0.986 | Probably Damaging | 3.42 | Benign | 0.02 | Affected | 0.1092 | 0.1326 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.3496G>C | A1166P 2D AIThe SynGAP1 missense variant A1166P 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, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as Pathogenic, whereas the SGM‑Consensus (majority vote) indicates Likely Benign; Foldetta results are unavailable. Overall, the predictions are mixed, with a slight bias toward benign, and there is no ClinVar entry to contradict the current assessment. Thus, the variant is most likely benign based on the collective evidence, though high‑accuracy tools provide conflicting signals. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.575842 | Disordered | 0.811691 | Binding | 0.381 | 0.803 | 0.375 | -2.890 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.468 | Likely Benign | -1.09 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 5.29 | Benign | 0.23 | Tolerated | 0.1774 | 0.4237 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| 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.1136C>T | S379L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379L is listed in ClinVar as Benign (ClinVar ID 1360860.0) and is present in gnomAD (ID 6‑33438041‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are Rosetta and SIFT. Foldetta and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence supports a benign impact, which is consistent with the ClinVar classification; there is no contradiction with the reported ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | Benign | 1 | 6-33438041-C-T | 8 | 4.05e-5 | -5.641 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.2 | 3.38 | Destabilizing | 1.89 | Ambiguous | -0.52 | Ambiguous | 0.469 | Likely Benign | -0.85 | Neutral | 0.015 | Benign | 0.002 | Benign | 3.83 | Benign | 0.04 | Affected | 4.32 | 11 | 0.1891 | 0.5644 | -3 | -2 | 4.6 | 26.08 | 251.9 | -48.1 | 0.6 | 1.1 | 0.0 | 0.5 | Uncertain | Ser379 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are observed in the variant simulations, Leu379 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effect on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||
| c.1147G>T | G383W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G383W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438052‑G‑T). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta as pathogenic. Because the majority of conventional predictors favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic interpretation. This conclusion does not conflict with the ClinVar uncertain status, which reflects the current lack of definitive clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | Uncertain | 1 | 6-33438052-G-T | 1 | 6.22e-7 | -10.161 | Likely Pathogenic | 0.439 | Ambiguous | Likely Benign | 5.81 | Destabilizing | 3.6 | 4.44 | Destabilizing | 5.13 | Destabilizing | 0.08 | Likely Benign | 0.469 | Likely Benign | -1.01 | Neutral | 0.959 | Probably Damaging | 0.704 | Possibly Damaging | 4.09 | Benign | 0.00 | Affected | 4.32 | 7 | 0.0972 | 0.3785 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||
| c.1256A>G | E419G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E419G is listed in ClinVar with an uncertain significance (ClinVar ID 2004834.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms likely pathogenic, and the Foldetta stability analysis is inconclusive. No evidence from FoldX, Rosetta, or premPS is available. Overall, the preponderance of predictions indicates that E419G is most likely pathogenic, which contrasts with the current ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | Uncertain | 1 | -10.589 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 1.41 | Ambiguous | 0.0 | 1.94 | Ambiguous | 1.68 | Ambiguous | 0.83 | Ambiguous | 0.469 | Likely Benign | -6.42 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.31 | Benign | 0.02 | Affected | 3.37 | 29 | 0.2992 | 0.5728 | 0 | -2 | 3.1 | -72.06 | 165.3 | 110.8 | 0.0 | 0.0 | -0.1 | 0.0 | X | Potentially Pathogenic | The carboxylate group of Glu419, located on an α helix (res. Met414-Glu436), forms a salt bridge with the side chain of either Arg716 or Lys418 from an opposing helix (res. Pro713-Arg726). The backbone amide group of Glu419 does not form H-bonds, resulting in a slight bend in the α helix. Thus, although glycine is known as an “α helix breaker,” the residue swap does not disrupt the continuity or integrity of the α helix. However, because Gly419 cannot form a salt bridge with the guanidinium group of the Arg716 side chain, the C2-GAP domain tertiary structure could be compromised during folding. | ||||||||||||||||
| c.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.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.1676G>C | C559S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C559S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: premPS (Uncertain) and AlphaMissense‑Optimized (Uncertain). High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta) as Benign, and AlphaMissense‑Optimized as Uncertain. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -10.756 | Likely Pathogenic | 0.785 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.0 | -0.31 | Likely Benign | -0.17 | Likely Benign | 0.65 | Ambiguous | 0.469 | Likely Benign | -7.26 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.58 | Benign | 0.64 | Tolerated | 0.3940 | 0.1319 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1895A>G | N632S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632S 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen2_HumDiv, and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions (six benign vs. three pathogenic) support a benign classification, 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. | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | -7.677 | In-Between | 0.291 | Likely Benign | Likely Benign | 0.81 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.80 | Ambiguous | 0.41 | Likely Benign | 0.469 | Likely Benign | -3.85 | Deleterious | 0.718 | Possibly Damaging | 0.086 | Benign | -1.37 | Pathogenic | 0.12 | Tolerated | 0.3302 | 0.6486 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| 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.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.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.1043T>A | V348E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348E is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from REVEL, while all other evaluated algorithms (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for V348E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -11.135 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.41 | Destabilizing | 0.1 | 2.20 | Destabilizing | 2.31 | Destabilizing | 2.14 | Destabilizing | 0.470 | Likely Benign | -5.26 | Deleterious | 0.989 | Probably Damaging | 0.637 | Possibly Damaging | 1.56 | Pathogenic | 0.01 | Affected | 0.1089 | 0.1922 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.2779T>G | F927V 2D AIThe SynGAP1 missense variant F927V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, 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 pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta results are unavailable and therefore not considered. Overall, the preponderance of evidence from multiple in silico predictors and high‑accuracy tools indicates that 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 | 0.529623 | Disordered | 0.985043 | Binding | 0.324 | 0.854 | 0.250 | -4.919 | Likely Benign | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.470 | Likely Benign | -5.21 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.34 | Pathogenic | 0.00 | Affected | 0.2207 | 0.1206 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||||||||||||
| c.3436C>T | P1146S 2D AIThe SynGAP1 missense variant P1146S is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33444471-C‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.732173 | Binding | 0.415 | 0.837 | 1.000 | 6-33444471-C-T | 2 | 1.24e-6 | -3.045 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.470 | Likely Benign | -3.66 | Deleterious | 0.945 | Possibly Damaging | 0.760 | Possibly Damaging | 5.52 | Benign | 0.00 | Affected | 4.32 | 4 | 0.3408 | 0.5186 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3458G>T | R1153L 2D AIThe SynGAP1 missense variant R1153L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. When predictions are grouped by consensus, the majority of algorithms (seven of nine) favor a deleterious effect, while only two suggest a benign outcome. High‑accuracy assessments further support a damaging interpretation: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta results are not available. Overall, the evidence points to a pathogenic impact for R1153L, 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 Pathogenic | 0.762850 | Disordered | 0.820118 | Binding | 0.361 | 0.848 | 0.625 | -3.595 | Likely Benign | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.470 | Likely Benign | -5.05 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.48 | Pathogenic | 0.00 | Affected | 0.1913 | 0.4400 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3689C>T | T1230I 2D AIThe SynGAP1 missense variant T1230I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of evidence (seven pathogenic vs. three benign predictions) points to a pathogenic impact. 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. | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -5.661 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.470 | Likely Benign | -2.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.43 | Benign | 0.02 | Affected | 0.0581 | 0.4898 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.815G>T | R272L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R272L 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, Rosetta, and premPS. Those that predict a pathogenic effect are 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 the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the majority of evaluated tools predict a pathogenic impact. 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 | C2 | 0.071867 | Structured | 0.425620 | Uncertain | 0.925 | 0.215 | 0.125 | -10.796 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 1.66 | Ambiguous | 0.3 | -0.46 | Likely Benign | 0.60 | Ambiguous | 0.41 | Likely Benign | 0.470 | Likely Benign | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 0.1691 | 0.4230 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1126G>A | G376S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G376S is reported in gnomAD (ID 6‑33438031‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from FoldX, polyPhen‑2 (HumDiv and HumVar), and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of evidence points to a benign effect; 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 Benign | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | 6-33438031-G-A | 1 | 6.21e-7 | -4.913 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 2.30 | Destabilizing | 0.5 | -0.45 | Likely Benign | 0.93 | Ambiguous | 0.32 | Likely Benign | 0.471 | Likely Benign | -0.73 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.33 | Pathogenic | 0.22 | Tolerated | 4.32 | 12 | 0.2831 | 0.4801 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||
| c.1130T>G | M377R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M377R is present in gnomAD (6‑33438035‑T‑G) and has no ClinVar entry. Prediction tools that report a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and Foldetta. The high‑accuracy consensus (SGM‑Consensus) is “Likely Benign,” derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—all of which are benign. AlphaMissense‑Optimized also predicts benign, whereas Foldetta predicts pathogenic. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict the ClinVar status (which is currently absent). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.675549 | Disordered | 0.431183 | Uncertain | 0.324 | 0.884 | 0.625 | 6-33438035-T-G | -3.150 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.49 | Likely Benign | 0.4 | 4.81 | Destabilizing | 2.65 | Destabilizing | 0.69 | Ambiguous | 0.471 | Likely Benign | -0.64 | Neutral | 0.004 | Benign | 0.009 | Benign | 5.46 | Benign | 0.18 | Tolerated | 4.32 | 12 | 0.2369 | 0.1918 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||||||
| c.1156G>T | G386W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G386W is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that classify the change as benign include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments give a benign verdict from AlphaMissense‑Optimized, a benign consensus from the SGM method (majority of the four contributing tools are benign), and a pathogenic result from Foldetta. Uncertain calls from AlphaMissense‑Default and Rosetta are treated as unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with the lack of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | -10.389 | Likely Pathogenic | 0.519 | Ambiguous | Likely Benign | 6.07 | Destabilizing | 5.5 | 1.28 | Ambiguous | 3.68 | Destabilizing | -0.23 | Likely Benign | 0.471 | Likely Benign | -0.85 | Neutral | 0.996 | Probably Damaging | 0.920 | Probably Damaging | 3.90 | Benign | 0.00 | Affected | 0.1058 | 0.4676 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| 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.1949A>C | N650T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650T 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, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results 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 inconclusive. 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 | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -13.626 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.31 | Likely Benign | 0.1 | 0.73 | Ambiguous | 0.52 | Ambiguous | 0.69 | Ambiguous | 0.471 | Likely Benign | -5.98 | Deleterious | 0.986 | Probably Damaging | 0.710 | Possibly Damaging | 3.04 | Benign | 0.01 | Affected | 0.1700 | 0.4843 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| 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.3128G>T | R1043M 2D AIThe SynGAP1 missense variant R1043M is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv and SIFT 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 further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for R1043M, 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 | 0.978672 | Disordered | 0.954069 | Binding | 0.299 | 0.853 | 0.625 | -4.800 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.471 | Likely Benign | -1.98 | Neutral | 0.744 | Possibly Damaging | 0.229 | Benign | 5.38 | Benign | 0.00 | Affected | 0.1982 | 0.4468 | 0 | -1 | 6.4 | -24.99 | |||||||||||||||||||||||||||||||||||||||
| c.3722T>C | L1241P 2D AIThe SynGAP1 missense variant L1241P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. 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 and the SGM‑Consensus as Likely Pathogenic; Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.545602 | Disordered | 0.488880 | Uncertain | 0.828 | 0.541 | 0.375 | -16.301 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.471 | Likely Benign | -5.42 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.61 | Pathogenic | 0.00 | Affected | 0.3640 | 0.1048 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| 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.874G>C | A292P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely converge on a deleterious effect: only REVEL classifies it as benign, whereas FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all 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) labels it Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a destabilizing, 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 | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -16.897 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.37 | Destabilizing | 0.3 | 9.80 | Destabilizing | 7.09 | Destabilizing | 1.23 | Destabilizing | 0.471 | Likely Benign | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.67 | Pathogenic | 0.01 | Affected | 0.2101 | 0.5988 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1942T>A | F648I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant F648I resides in the GAP domain. ClinVar contains no entry for this change, and it is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—report a pathogenic or likely pathogenic outcome. High‑accuracy assessments 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) also yields a pathogenic prediction. Taken together, the evidence overwhelmingly supports a pathogenic classification for F648I, 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 Pathogenic | GAP | 0.051831 | Structured | 0.346782 | Uncertain | 0.943 | 0.339 | 0.000 | -11.912 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.49 | Destabilizing | 0.1 | 2.49 | Destabilizing | 2.49 | Destabilizing | 1.05 | Destabilizing | 0.472 | Likely Benign | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.04 | Affected | 0.1673 | 0.1955 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.3416A>T | Q1139L 2D AIThe SynGAP1 missense variant Q1139L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, PROVEAN and SIFT predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. 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 | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -1.689 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.472 | Likely Benign | -3.75 | Deleterious | 0.224 | Benign | 0.237 | Benign | 5.30 | Benign | 0.00 | Affected | 0.0745 | 0.5599 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3488A>G | H1163R 2D AIThe SynGAP1 missense variant H1163R 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, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and no Foldetta stability data is available. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | -2.505 | Likely Benign | 0.942 | Likely Pathogenic | Ambiguous | 0.472 | Likely Benign | -2.08 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.43 | Benign | 0.27 | Tolerated | 0.1863 | 0.2402 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.3590A>T | E1197V 2D AIThe SynGAP1 missense variant E1197V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑vs‑2 tie and therefore unavailable; Foldetta, which would combine FoldX‑MD and Rosetta outputs, has no reported result. Overall, the balance of evidence (five pathogenic versus three benign predictions, with one uncertain) indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -6.298 | Likely Benign | 0.923 | Likely Pathogenic | Ambiguous | 0.472 | Likely Benign | -3.28 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.40 | Benign | 0.03 | Affected | 0.0440 | 0.5320 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.623C>G | P208R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P208R 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. The majority of other in silico predictors (FoldX, premPS, 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, while Rosetta remains uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, with no contradiction to ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.271506 | Structured | 0.399506 | Uncertain | 0.864 | 0.345 | 0.125 | -11.929 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 5.25 | Destabilizing | 1.6 | 1.39 | Ambiguous | 3.32 | Destabilizing | 1.16 | Destabilizing | 0.472 | Likely Benign | -7.50 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.75 | Benign | 0.00 | Affected | 0.1676 | 0.3118 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| 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.862G>T | D288Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, and premPS; pathogenic predictions from SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus confirms Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from the available tools suggests a benign effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -15.269 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.11 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.61 | Ambiguous | 0.10 | Likely Benign | 0.472 | Likely Benign | -7.11 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | 0.0635 | 0.5009 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.988G>T | D330Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D330Y 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 REVEL and premPS, whereas the remaining tools—including SGM‑Consensus, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and therefore not counted. High‑accuracy methods all support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates that D330Y 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 | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -14.200 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 1.98 | Ambiguous | 0.6 | 2.90 | Destabilizing | 2.44 | Destabilizing | 0.35 | Likely Benign | 0.472 | Likely Benign | -6.47 | Deleterious | 0.998 | Probably Damaging | 0.948 | Probably Damaging | 0.89 | Pathogenic | 0.00 | Affected | 0.0539 | 0.4689 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1728C>G | C576W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C576W is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of other in silico predictors (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the 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). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.017684 | Uncertain | 0.913 | 0.245 | 0.000 | -14.796 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 13.87 | Destabilizing | 1.5 | 5.46 | Destabilizing | 9.67 | Destabilizing | 0.60 | Ambiguous | 0.473 | Likely Benign | -10.01 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.38 | Benign | 0.00 | Affected | 0.1894 | 0.3017 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.3719G>C | R1240P 2D AIThe SynGAP1 missense variant R1240P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the collective evidence, the variant is most likely pathogenic, 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 Pathogenic | Coiled-coil | 0.541878 | Disordered | 0.511333 | Binding | 0.865 | 0.540 | 0.375 | -16.120 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.473 | Likely Benign | -5.45 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.2037 | 0.3768 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||
| c.1448T>C | I483T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I483T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts a pathogenic effect. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.415850 | Uncertain | 0.798 | 0.254 | 0.000 | -10.692 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.32 | Destabilizing | 0.0 | 2.05 | Destabilizing | 2.19 | Destabilizing | 1.77 | Destabilizing | 0.474 | Likely Benign | -4.24 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.15 | Benign | 0.05 | Affected | 0.0888 | 0.0840 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| 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.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.646C>G | Q216E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216E 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, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains 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. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -9.215 | Likely Pathogenic | 0.550 | Ambiguous | Likely Benign | 0.49 | Likely Benign | 0.3 | 0.30 | Likely Benign | 0.40 | Likely Benign | 0.35 | Likely Benign | 0.474 | Likely Benign | -1.89 | Neutral | 0.779 | Possibly Damaging | 0.351 | Benign | 5.85 | Benign | 0.13 | Tolerated | 0.1872 | 0.3117 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.729T>G | I243M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243M has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on 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 scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign”; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -4.305 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.13 | Likely Benign | -0.01 | Likely Benign | 0.474 | Likely Benign | 0.58 | Neutral | 0.985 | Probably Damaging | 0.798 | Possibly Damaging | 5.61 | Benign | 0.94 | Tolerated | 0.0553 | 0.2200 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.735T>A | N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM, aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a majority pathogenic verdict. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Overall, the majority of individual predictors and the SGM consensus favor a pathogenic effect, while Foldetta and a subset of benign tools suggest stability preservation. Given the predominance of pathogenic predictions and the absence of ClinVar annotation, the variant is most likely pathogenic and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.110 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.32 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.16 | Likely Benign | 0.83 | Ambiguous | 0.474 | Likely Benign | -4.86 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.88 | Benign | 0.01 | Affected | 0.2271 | 0.5645 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.735T>G | N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a Benign effect. Overall, the preponderance of evidence—including the high‑accuracy tools—points to a pathogenic impact for N245K, 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 | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.110 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.32 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.16 | Likely Benign | 0.83 | Ambiguous | 0.474 | Likely Benign | -4.86 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.88 | Benign | 0.01 | Affected | 0.2271 | 0.5645 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| 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.1150G>C | G384R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G384R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, PROVEAN, and AlphaMissense‑Optimized, whereas pathogenic calls are made by FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, but SGM‑Consensus and Foldetta both predict pathogenic, with Foldetta integrating FoldX‑MD and Rosetta stability outputs. Overall, the majority of evidence points to 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 | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | -9.186 | Likely Pathogenic | 0.719 | Likely Pathogenic | Likely Benign | 2.16 | Destabilizing | 0.4 | 5.06 | Destabilizing | 3.61 | Destabilizing | 0.25 | Likely Benign | 0.475 | Likely Benign | -0.96 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.02 | Affected | 0.1250 | 0.4156 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| 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.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.1893G>C | Q631H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631H is reported in gnomAD (6‑33440945‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of other in silico predictors (Rosetta, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) all indicate a pathogenic impact. 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 uncertain. 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 classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | 6-33440945-G-C | 2 | 1.24e-6 | -13.282 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.84 | Ambiguous | 0.2 | 2.21 | Destabilizing | 1.53 | Ambiguous | 0.84 | Ambiguous | 0.475 | Likely Benign | -4.98 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 3.37 | 34 | 0.0834 | 0.1757 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||
| c.1893G>T | Q631H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631H is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FATHMM, whereas the majority of algorithms—including AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, Rosetta, and the SGM Consensus—classify the change as pathogenic. Predictions from 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, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is uncertain. Overall, the preponderance of evidence points to a pathogenic impact for Q631H, which is consistent with the absence of a benign ClinVar annotation and the lack of population data in gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -13.282 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.84 | Ambiguous | 0.2 | 2.21 | Destabilizing | 1.53 | Ambiguous | 0.84 | Ambiguous | 0.475 | Likely Benign | -4.98 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 3.37 | 34 | 0.0834 | 0.1757 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||
| c.2774T>A | L925H 2D AIThe SynGAP1 missense variant L925H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic.” No Foldetta stability result is available. Overall, the majority of evidence points to a pathogenic effect for L925H, 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 | 0.483068 | Structured | 0.977963 | Binding | 0.290 | 0.852 | 0.125 | -3.369 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.475 | Likely Benign | -5.24 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.1219 | 0.1494 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||||||||||||
| c.3508A>C | S1170R 2D AIThe SynGAP1 missense variant S1170R 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, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the high‑accuracy consensus is split. Thus, the variant is most likely pathogenic based on the preponderance of 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 Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -1.451 | Likely Benign | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.475 | Likely Benign | -1.89 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 5.39 | Benign | 0.04 | Affected | 0.0770 | 0.3444 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.875C>A | A292E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A292E is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. 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 A292E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -14.282 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.07 | Destabilizing | 1.2 | 3.82 | Destabilizing | 4.95 | Destabilizing | 1.54 | Destabilizing | 0.475 | Likely Benign | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.02 | Affected | 0.1444 | 0.2205 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.931C>A | H311N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311N 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, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, 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 evaluated tools predict pathogenicity, suggesting that H311N is most likely pathogenic. This prediction 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 | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -9.545 | Likely Pathogenic | 0.661 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.1 | 1.12 | Ambiguous | 0.97 | Ambiguous | 0.72 | Ambiguous | 0.475 | Likely Benign | -5.35 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.89 | Pathogenic | 0.06 | Tolerated | 0.1566 | 0.2380 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| 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.1997A>T | E666V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E666V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools show mixed results: benign calls come from REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the 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 a benign effect. FoldX alone is uncertain. Overall, the majority of tools and the high‑accuracy consensus favor a pathogenic interpretation, with no conflict from ClinVar status because no classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.086870 | Uncertain | 0.925 | 0.387 | 0.000 | -10.870 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.61 | Ambiguous | 0.1 | 0.08 | Likely Benign | 0.35 | Likely Benign | 0.31 | Likely Benign | 0.476 | Likely Benign | -5.95 | Deleterious | 0.575 | Possibly Damaging | 0.214 | Benign | 3.44 | Benign | 0.03 | Affected | 0.0818 | 0.5613 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.2093A>C | E698A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E698A 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, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. No prediction or folding result is missing. Overall, the majority of tools (seven versus six) favor a pathogenic interpretation, and this 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 | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -10.962 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.31 | Likely Benign | 0.0 | 0.26 | Likely Benign | 0.29 | Likely Benign | 0.25 | Likely Benign | 0.476 | Likely Benign | -5.57 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | 0.3147 | 0.4160 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.3122C>A | P1041H 2D AIThe SynGAP1 missense variant P1041H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT; AlphaMissense‑Default is uncertain. 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’s protein‑folding stability result is unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status because the variant has not been reported there. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.962114 | Disordered | 0.967463 | Binding | 0.345 | 0.833 | 0.625 | -5.312 | Likely Benign | 0.377 | Ambiguous | Likely Benign | 0.476 | Likely Benign | -3.32 | Deleterious | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 5.45 | Benign | 0.03 | Affected | 0.1883 | 0.5434 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||||
| c.3389A>T | K1130M 2D AIThe SynGAP1 K1130M missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign outcome. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the balance of evidence leans toward a benign classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for K1130M. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.863782 | Binding | 0.350 | 0.904 | 0.750 | -4.844 | Likely Benign | 0.858 | Likely Pathogenic | Ambiguous | 0.476 | Likely Benign | -1.62 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 5.42 | Benign | 0.00 | Affected | 0.1703 | 0.4407 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.3487C>G | H1163D 2D AISynGAP1 missense variant H1163D is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, ESM1b, and FATHMM, while pathogenic calls come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized rates the variant as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a tie and is therefore unavailable, and Foldetta folding‑stability analysis is not provided. With an equal number of benign and pathogenic predictions and no decisive high‑accuracy evidence, the variant remains ambiguous. Thus, it is most likely neither clearly benign nor pathogenic, and this uncertainty aligns with its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.858469 | Binding | 0.328 | 0.825 | 0.375 | Uncertain | 1 | -2.107 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.476 | Likely Benign | -2.60 | Deleterious | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.44 | Benign | 0.31 | Tolerated | 3.88 | 3 | 0.2145 | 0.1986 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||||
| c.940T>C | F314L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314L 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 ESM1b, whereas the majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results and 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. Overall, the preponderance of evidence indicates that F314L is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -6.004 | Likely Benign | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.87 | Ambiguous | 0.1 | 0.82 | Ambiguous | 0.85 | Ambiguous | 1.21 | Destabilizing | 0.476 | Likely Benign | -4.85 | Deleterious | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.30 | Pathogenic | 0.05 | Affected | 0.2204 | 0.3089 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1037T>C | V346A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346A is reported in gnomAD (6‑33437942‑T‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect are limited to REVEL, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | 6-33437942-T-C | 1 | 6.20e-7 | -8.556 | Likely Pathogenic | 0.856 | Likely Pathogenic | Ambiguous | 2.72 | Destabilizing | 0.2 | 2.73 | Destabilizing | 2.73 | Destabilizing | 1.92 | Destabilizing | 0.477 | Likely Benign | -3.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 3.37 | 25 | 0.3341 | 0.2967 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||
| c.1087T>A | Y363N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y363N 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 algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify Y363N 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 (majority vote) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. 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 | C2 | 0.321458 | Structured | 0.435392 | Uncertain | 0.954 | 0.586 | 0.125 | -12.121 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 2.06 | Destabilizing | 0.1 | 2.85 | Destabilizing | 2.46 | Destabilizing | 1.45 | Destabilizing | 0.477 | Likely Benign | -8.04 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.55 | Pathogenic | 0.01 | Affected | 0.3117 | 0.2021 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| 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.3523C>G | R1175G 2D AIThe SynGAP1 missense variant R1175G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. 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 Uncertain, and Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.538167 | Disordered | 0.589347 | Binding | 0.545 | 0.732 | 0.375 | -4.888 | Likely Benign | 0.865 | Likely Pathogenic | Ambiguous | 0.477 | Likely Benign | -1.64 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.35 | Benign | 0.00 | Affected | 0.3006 | 0.2350 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3580A>G | R1194G 2D AIThe SynGAP1 missense variant R1194G 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, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are unavailable. Overall, the majority of conventional tools lean toward pathogenicity, and the high‑accuracy predictions are split, with no ClinVar evidence to contradict the pathogenic interpretation. Thus, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.685117 | Disordered | 0.425297 | Uncertain | 0.796 | 0.602 | 0.375 | -6.849 | Likely Benign | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.477 | Likely Benign | -2.17 | Neutral | 0.991 | Probably Damaging | 0.991 | Probably Damaging | 5.56 | Benign | 0.02 | Affected | 0.3275 | 0.2847 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.654C>A | F218L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218L 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), Rosetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta are inconclusive and are treated as unavailable. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts Likely Pathogenic; Foldetta remains 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 | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.861 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.4 | 2.36 | Destabilizing | 1.66 | Ambiguous | 1.08 | Destabilizing | 0.477 | Likely Benign | -3.80 | Deleterious | 0.158 | Benign | 0.025 | Benign | 5.90 | Benign | 0.15 | Tolerated | 0.2331 | 0.3241 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.654C>G | F218L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218L 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), Rosetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta are inconclusive and are treated as unavailable. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts Likely Pathogenic; Foldetta remains 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 | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.861 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.4 | 2.36 | Destabilizing | 1.66 | Ambiguous | 1.08 | Destabilizing | 0.477 | Likely Benign | -3.80 | Deleterious | 0.158 | Benign | 0.025 | Benign | 5.90 | Benign | 0.15 | Tolerated | 0.2331 | 0.3241 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1752C>G | I584M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I584M is listed in ClinVar with an uncertain significance (ClinVar ID 1301269.0) and is present in gnomAD (6‑33440804‑C‑G). Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized, whereas pathogenic calls arise from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts benign, but SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the majority of tools favor pathogenicity, and the high‑accuracy consensus leans pathogenic, indicating the variant is most likely pathogenic, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | Uncertain | 2 | 6-33440804-C-G | 1 | 6.20e-7 | -10.119 | Likely Pathogenic | 0.419 | Ambiguous | Likely Benign | 0.11 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.29 | Likely Benign | 1.16 | Destabilizing | 0.478 | Likely Benign | -2.62 | Deleterious | 0.983 | Probably Damaging | 0.925 | Probably Damaging | -1.25 | Pathogenic | 0.12 | Tolerated | 3.37 | 34 | 0.0777 | 0.2127 | 2 | 1 | -2.6 | 18.03 | 247.5 | -20.3 | -0.1 | 0.3 | -0.1 | 0.1 | X | Potentially Benign | A hydrophobic residue, Ile584, located in an α helix (res. Glu582-Met603), is swapped for another hydrophobic residue, Met584. The sec-butyl hydrocarbon side chain of Ile584 packs hydrophobically with residues in an inter-helix hydrophobic space (e.g., Leu588, Met477, Val473, and Ile483).In the variant simulations, the thioether hydrophobic side chain of Met584 maintains similar interactions as Ile584 in the WT, as it is roughly the same size and fits well within the hydrophobic space. Thus, the residue swap does not appear to cause any negative effects on the protein structure. | |||||||||||||
| c.1906T>C | F636L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions are made by 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, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus confirms Likely Pathogenic, and the Foldetta stability analysis is inconclusive. Other stability tools (FoldX, Rosetta, premPS) are uncertain. Based on the preponderance of pathogenic predictions and the consensus from high‑accuracy methods, 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 | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -11.871 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.88 | Ambiguous | 0.1 | 0.69 | Ambiguous | 0.79 | Ambiguous | 0.71 | Ambiguous | 0.478 | Likely Benign | -5.78 | Deleterious | 0.994 | Probably Damaging | 0.952 | Probably Damaging | 3.60 | Benign | 0.22 | Tolerated | 0.1853 | 0.3024 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.3176G>T | G1059V 2D AIThe SynGAP1 missense variant G1059V is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the majority‑vote SGM‑Consensus also classifies it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy tools corroborate the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for G1059V, and this assessment does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | -7.242 | In-Between | 0.106 | Likely Benign | Likely Benign | 0.478 | Likely Benign | -0.82 | Neutral | 0.259 | Benign | 0.066 | Benign | 2.54 | Benign | 0.00 | Affected | 0.1462 | 0.3494 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3471G>C | W1157C 2D AIThe SynGAP1 missense variant W1157C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that W1157C 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 | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -4.730 | Likely Benign | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.478 | Likely Benign | -9.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.04 | Pathogenic | 0.00 | Affected | 0.3927 | 0.1406 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||||||||||||
| c.3471G>T | W1157C 2D AIThe SynGAP1 missense variant W1157C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that W1157C 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 | 0.694846 | Disordered | 0.877471 | Binding | 0.364 | 0.861 | 0.375 | -4.730 | Likely Benign | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.478 | Likely Benign | -9.46 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.04 | Pathogenic | 0.00 | Affected | 0.3927 | 0.1406 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||||||||||||
| c.3559A>G | M1187V 2D AIThe M1187V missense change in SynGAP1’s coiled‑coil domain is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and 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. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -3.107 | Likely Benign | 0.733 | Likely Pathogenic | Likely Benign | 0.478 | Likely Benign | -1.44 | Neutral | 0.843 | Possibly Damaging | 0.926 | Probably Damaging | 5.49 | Benign | 0.19 | Tolerated | 0.3300 | 0.2800 | 2 | 1 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||||||
| c.1013A>C | D338A 2D 3DClick to see structure in 3D Viewer AISynGAP1 D338A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, polyPhen‑2 HumVar, and SIFT, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. 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 toward 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 | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -10.639 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 1.22 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.17 | Ambiguous | 0.16 | Likely Benign | 0.479 | Likely Benign | -5.74 | Deleterious | 0.625 | Possibly Damaging | 0.192 | Benign | 1.73 | Pathogenic | 0.11 | Tolerated | 0.3830 | 0.5988 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.1199T>C | V400A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V400A is not reported in ClinVar and is absent from gnomAD. Consensus from standard predictors shows a split: benign calls from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls come from FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT and AlphaMissense‑Default. Two high‑accuracy tools give a clear signal: AlphaMissense‑Optimized is uncertain, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta also predicts pathogenic. With most evidence pointing to deleterious effects, the variant is most likely pathogenic, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -7.564 | In-Between | 0.871 | Likely Pathogenic | Ambiguous | 3.14 | Destabilizing | 0.1 | 3.12 | Destabilizing | 3.13 | Destabilizing | 2.29 | Destabilizing | 0.479 | Likely Benign | -3.12 | Deleterious | 0.435 | Benign | 0.049 | Benign | 5.32 | Benign | 0.01 | Affected | 0.3291 | 0.2767 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| 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.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.1873C>T | L625F 2D AIThe SynGAP1 missense variant L625F is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that predict a pathogenic effect include SGM‑Consensus (Likely Pathogenic), Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are uncertain or inconclusive are FoldX, premPS, and Foldetta. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is 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 | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | -12.989 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 1.3 | 2.26 | Destabilizing | 1.98 | Ambiguous | 0.74 | Ambiguous | 0.479 | Likely Benign | -3.82 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.01 | Benign | 0.01 | Affected | 0.0586 | 0.2998 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1991T>G | L664W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: benign calls are made only by REVEL and FATHMM, whereas the remaining 13 predictors—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a pathogenic effect. 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 | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -17.438 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 7.81 | Destabilizing | 0.5 | 3.17 | Destabilizing | 5.49 | Destabilizing | 1.57 | Destabilizing | 0.479 | Likely Benign | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.984 | Probably Damaging | 2.84 | Benign | 0.00 | Affected | 0.0543 | 0.2272 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.3563A>T | D1188V 2D AIThe SynGAP1 D1188V 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, ESM1b, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2), and Foldetta results are unavailable. 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. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -4.482 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.479 | Likely Benign | -4.13 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 5.49 | Benign | 0.00 | Affected | 0.0592 | 0.4651 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.814C>G | R272G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R272G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions are limited to REVEL, whereas pathogenic predictions are made by FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results come from Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.071867 | Structured | 0.425620 | Uncertain | 0.925 | 0.215 | 0.125 | -11.540 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 3.40 | Destabilizing | 0.0 | 1.94 | Ambiguous | 2.67 | Destabilizing | 1.06 | Destabilizing | 0.479 | Likely Benign | -4.57 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.01 | Affected | 0.3082 | 0.3062 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1438G>C | E480Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 E480Q is not reported in ClinVar (no ClinVar ID) and is present in gnomAD (ID 6‑33438470‑G‑C). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and the protein‑folding stability method Foldetta. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). AlphaMissense‑Optimized is uncertain and therefore not used as evidence. High‑accuracy assessments show Foldetta predicts benign stability change, SGM Consensus predicts pathogenic, and AlphaMissense‑Optimized is inconclusive. Overall, the predictions are split, but the presence of a benign prediction from a high‑accuracy folding method and the lack of a ClinVar pathogenic claim suggest the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.216401 | Structured | 0.426867 | Uncertain | 0.798 | 0.250 | 0.000 | 6-33438470-G-C | 2 | 1.24e-6 | -12.336 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.0 | -0.01 | Likely Benign | 0.21 | Likely Benign | 0.75 | Ambiguous | 0.480 | Likely Benign | -2.29 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | -1.29 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 0.0854 | 0.6870 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||
| c.1873C>G | L625V 2D AISynGAP1 missense variant L625V is listed in ClinVar with an uncertain significance (ClinVar ID 3392716.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.045896 | Uncertain | 0.966 | 0.215 | 0.000 | Uncertain | 1 | -11.319 | Likely Pathogenic | 0.833 | Likely Pathogenic | Ambiguous | 1.80 | Ambiguous | 0.7 | 1.69 | Ambiguous | 1.75 | Ambiguous | 1.42 | Destabilizing | 0.480 | Likely Benign | -2.96 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.1306 | 0.3427 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||
| c.2093A>T | E698V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E698V missense variant 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, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports an uncertain result. Overall, the majority of evidence points to a pathogenic impact for E698V, 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 | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -12.797 | Likely Pathogenic | 0.945 | Likely Pathogenic | Ambiguous | 0.76 | Ambiguous | 0.0 | 0.39 | Likely Benign | 0.58 | Ambiguous | 0.26 | Likely Benign | 0.480 | Likely Benign | -6.51 | Deleterious | 0.992 | Probably Damaging | 0.967 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.0577 | 0.4546 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.3578A>G | D1193G 2D AIThe SynGAP1 D1193G missense variant is catalogued in gnomAD (ID 6‑33444613‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) also favors benign. Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | 6-33444613-A-G | 1 | 6.21e-7 | -6.506 | Likely Benign | 0.765 | Likely Pathogenic | Likely Benign | 0.480 | Likely Benign | -2.27 | Neutral | 0.924 | Possibly Damaging | 0.652 | Possibly Damaging | 5.42 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2695 | 0.4765 | -1 | 1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||
| c.1460A>C | N487T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as “Likely Pathogenic.” High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No evidence from FoldX, Rosetta, or premPS is available to alter this assessment. Overall, the preponderance of computational evidence 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 | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -12.618 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 1.92 | Ambiguous | 0.1 | 1.94 | Ambiguous | 1.93 | Ambiguous | 0.68 | Ambiguous | 0.481 | Likely Benign | -5.97 | Deleterious | 0.987 | Probably Damaging | 0.980 | Probably Damaging | 2.78 | Benign | 0.05 | Affected | 0.1200 | 0.3441 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.1742G>A | R581Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R581Q is reported in ClinVar as benign (ClinVar ID 1388591.0) and is present in gnomAD (ID 6‑33440794‑G‑A). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta as benign. No other high‑confidence stability predictions are available. Overall, the predictions are mixed, with a slight bias toward benign outcomes from the majority of tools and the high‑accuracy AlphaMissense‑Optimized and Foldetta results. Therefore, the variant is most likely benign based on the current computational evidence, which is consistent with its ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.029544 | Uncertain | 0.829 | 0.236 | 0.000 | Benign | 1 | 6-33440794-G-A | 8 | 4.96e-6 | -7.584 | In-Between | 0.673 | Likely Pathogenic | Likely Benign | 1.31 | Ambiguous | 0.1 | -0.42 | Likely Benign | 0.45 | Likely Benign | 0.88 | Ambiguous | 0.481 | Likely Benign | -2.77 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.21 | Pathogenic | 0.11 | Tolerated | 3.37 | 34 | 0.2742 | 0.1851 | 1 | 1 | 1.0 | -28.06 | 239.6 | 53.5 | -0.2 | 0.2 | -0.4 | 0.1 | X | Potentially Pathogenic | Arg581 is located on a short α-α loop between two α helices (res. Arg563-Glu578 and res. Glu582-Ser604). In the WT simulations, the guanidinium group of Arg581 forms salt bridges with the carboxylate groups of Asp583 within the same helix, as well as with Glu478 and/or Glu480 on a slightly α-helical loop (res. Glu478-Thr488) preceding another α helix (res. Ala461-Phe476).In the variant simulations, the neutral carboxamide group of the Gln581 side chain cannot form any of these salt bridges. Instead, it packs hydrophobically against Met477 and Ile587 or forms hydrogen bonds sporadically with nearby residues (e.g., Asp583, Arg587). Thus, although no drastic changes are observed in the variant simulations, the residue swap could weaken the tertiary structure assembly. | |||||||||||||
| 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.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.2780T>C | F927S 2D  AIThe SynGAP1 missense variant F927S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome (3 pathogenic vs. 1 benign). AlphaMissense‑Optimized alone predicts pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the preponderance of pathogenic predictions—including the high‑accuracy consensus—the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.529623 | Disordered | 0.985043 | Binding | 0.324 | 0.854 | 0.250 | -5.480 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.481 | Likely Benign | -5.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.32 | Pathogenic | 0.00 | Affected | 0.4748 | 0.0591 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3530A>T | E1177V 2D AIThe SynGAP1 E1177V 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, ESM1b, and FATHMM, while those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, more tools predict pathogenicity (5) than benignity (3), and no ClinVar evidence contradicts 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. | Coiled-coil | 0.541878 | Disordered | 0.566503 | Binding | 0.542 | 0.705 | 0.250 | -3.091 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.481 | Likely Benign | -2.90 | Deleterious | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 5.66 | Benign | 0.01 | Affected | 0.0463 | 0.4520 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.863A>T | D288V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by REVEL and premPS, whereas the remaining tools—FoldX (uncertain), Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—all indicate a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic based on the aggregate predictions, 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 | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -15.812 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 1.74 | Ambiguous | 0.5 | 5.44 | Destabilizing | 3.59 | Destabilizing | 0.13 | Likely Benign | 0.481 | Likely Benign | -7.14 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.63 | Pathogenic | 0.05 | Affected | 0.0838 | 0.5545 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.970C>T | R324W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R324W is listed in ClinVar with an uncertain significance (ClinVar ID 845180.0) and is present in gnomAD (ID 6‑33437875‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from 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, is pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability or functional scores are available. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a leaning toward pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | Uncertain | 1 | 6-33437875-C-T | 2 | 1.24e-6 | -12.906 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 0.56 | Ambiguous | 1.03 | Ambiguous | 0.66 | Ambiguous | 0.481 | Likely Benign | -3.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.82 | Pathogenic | 0.16 | Tolerated | 3.39 | 22 | 0.1517 | 0.4361 | 2 | -3 | 3.6 | 30.03 | 256.6 | 39.1 | 0.0 | 0.1 | 0.3 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg324, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces outward and frequently forms a salt bridge with the carboxylate group of the Asp288 side chain, which is part of a β strand end (res. Met289-Pro298). In the variant simulations, the indole ring of the Trp324 side chain cannot maintain a similar interaction with the negatively charged carboxylate side chain of Asp288, potentially compromising the folding of the anti-parallel β sheet assembly. However, the residue swap does not appear to negatively impact the protein structure or its integrity based on the simulations. | |||||||||||||
| c.1015A>G | K339E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and premPS. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to 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 | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -14.284 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.13 | Likely Benign | 0.1 | -0.03 | Likely Benign | 0.05 | Likely Benign | 0.40 | Likely Benign | 0.482 | Likely Benign | -3.00 | Deleterious | 0.939 | Possibly Damaging | 0.670 | Possibly Damaging | 1.92 | Pathogenic | 0.03 | Affected | 0.3421 | 0.0882 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1082A>C | Q361P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q361P is listed in ClinVar as Pathogenic (ClinVar ID 3235087.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and premPS. All other evaluated algorithms—FoldX, Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy methods specifically give a pathogenic verdict: 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 of these predictions, the variant is most likely pathogenic, which is consistent with its ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.427593 | Uncertain | 0.945 | 0.534 | 0.250 | Likely Pathogenic | 1 | -13.280 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 3.12 | Destabilizing | 0.0 | 3.45 | Destabilizing | 3.29 | Destabilizing | 0.38 | Likely Benign | 0.482 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.979 | Probably Damaging | 1.63 | Pathogenic | 0.05 | Affected | 3.37 | 25 | 0.1986 | 0.5151 | -1 | 0 | 1.9 | -31.01 | |||||||||||||||||||||||||
| c.1181A>C | K394T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394T 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 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are PROVEAN, SIFT, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, the balance of evidence (five benign versus three pathogenic predictions) suggests 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. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -6.487 | Likely Benign | 0.599 | Likely Pathogenic | Likely Benign | 0.50 | Ambiguous | 0.1 | 2.46 | Destabilizing | 1.48 | Ambiguous | 0.57 | Ambiguous | 0.482 | Likely Benign | -3.35 | Deleterious | 0.247 | Benign | 0.166 | Benign | 4.61 | Benign | 0.01 | Affected | 0.2727 | 0.4453 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||
| 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.844T>G | C282G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C282G is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms 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 of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus is pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among pathogenic predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.348535 | Uncertain | 0.942 | 0.250 | 0.000 | -15.830 | Likely Pathogenic | 0.837 | Likely Pathogenic | Ambiguous | 2.60 | Destabilizing | 0.1 | 2.83 | Destabilizing | 2.72 | Destabilizing | 1.60 | Destabilizing | 0.482 | Likely Benign | -11.03 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.64 | Pathogenic | 0.04 | Affected | 0.3229 | 0.2238 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.1492A>G | M498V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M498V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (FoldX, Foldetta, premPS, polyPhen‑2 HumDiv, SIFT, FATHMM). Rosetta is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta predicts a pathogenic effect on protein stability. Overall, the majority of predictions lean toward a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.092881 | Structured | 0.399612 | Uncertain | 0.932 | 0.158 | 0.000 | -3.229 | Likely Benign | 0.317 | Likely Benign | Likely Benign | 2.74 | Destabilizing | 0.1 | 1.26 | Ambiguous | 2.00 | Destabilizing | 1.17 | Destabilizing | 0.483 | Likely Benign | -1.82 | Neutral | 0.752 | Possibly Damaging | 0.279 | Benign | -1.28 | Pathogenic | 0.04 | Affected | 0.2737 | 0.2737 | 2 | 1 | 2.3 | -32.06 | |||||||||||||||||||||||||||||
| 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.3559A>C | M1187L 2D AIThe SynGAP1 missense variant M1187L 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, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the majority of predictions and the high‑accuracy 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 | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -2.192 | Likely Benign | 0.772 | Likely Pathogenic | Likely Benign | 0.483 | Likely Benign | -1.27 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 5.48 | Benign | 1.00 | Tolerated | 0.1680 | 0.3637 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3559A>T | M1187L 2D AIThe SynGAP1 missense variant M1187L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign effect for M1187L, 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 | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -2.192 | Likely Benign | 0.772 | Likely Pathogenic | Likely Benign | 0.483 | Likely Benign | -1.27 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 5.48 | Benign | 1.00 | Tolerated | 0.1680 | 0.3637 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3785T>G | I1262S 2D AIThe SynGAP1 missense variant I1262S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—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 predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus also reports it as likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for I1262S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.497853 | Structured | 0.707863 | Binding | 0.886 | 0.576 | 0.125 | -15.167 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.483 | Likely Benign | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.2943 | 0.1110 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| 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.2153T>G | L718R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L718R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, which scores the variant as benign. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy 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, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming agreement among these tools, 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 | 0.298791 | Structured | 0.438417 | Uncertain | 0.966 | 0.385 | 0.000 | -16.119 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.90 | Destabilizing | 0.2 | 5.05 | Destabilizing | 5.48 | Destabilizing | 2.57 | Destabilizing | 0.484 | Likely Benign | -5.69 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.1254 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.3577G>T | D1193Y 2D AIThe SynGAP1 missense variant D1193Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the overall pattern of 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 | Coiled-coil | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | -8.233 | Likely Pathogenic | 0.883 | Likely Pathogenic | Ambiguous | 0.484 | Likely Benign | -2.94 | Deleterious | 0.992 | Probably Damaging | 0.947 | Probably Damaging | 5.50 | Benign | 0.00 | Affected | 0.0477 | 0.4111 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||
| 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.854G>A | C285Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and Rosetta. Those that agree on a pathogenic effect include SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are Foldetta, premPS, ESM1b, 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 evidence points to a pathogenic impact for C285Y. 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 | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.210 | In-Between | 0.895 | Likely Pathogenic | Ambiguous | 3.66 | Destabilizing | 1.1 | -2.33 | Stabilizing | 0.67 | Ambiguous | 0.53 | Ambiguous | 0.484 | Likely Benign | -8.67 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.18 | Tolerated | 0.1413 | 0.3689 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.860A>C | D287A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D287A is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta) as benign. The overall tally favors pathogenicity (8 tools vs 5 benign), but the conflicting high‑accuracy results leave uncertainty. Thus, the variant is most likely pathogenic according to the majority of predictions, which does not contradict its ClinVar Uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | Uncertain | 1 | -14.686 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.1 | -0.04 | Likely Benign | 0.13 | Likely Benign | 0.40 | Likely Benign | 0.484 | Likely Benign | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.58 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 0.4448 | 0.7431 | -2 | 0 | 5.3 | -44.01 | |||||||||||||||||||||||||
| c.995A>T | D332V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332V 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, and premPS, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results come from FoldX, Rosetta, and AlphaMissense‑Optimized. 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 favors a pathogenic classification; 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 Pathogenic | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -13.710 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 1.39 | Ambiguous | 0.1 | -0.52 | Ambiguous | 0.44 | Likely Benign | 0.50 | Likely Benign | 0.484 | Likely Benign | -7.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.21 | Pathogenic | 0.03 | Affected | 0.0573 | 0.4132 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1226T>G | M409R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409R is not reported in ClinVar and is present in gnomAD (ID 6‑33438131‑T‑G). Functional prediction tools cluster into two groups: benign (REVEL, SIFT, FATHMM, Rosetta) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default). Three tools give uncertain results (FoldX, Foldetta, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the balance of evidence favors a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | 6-33438131-T-G | -12.795 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 1.47 | Ambiguous | 0.4 | 0.44 | Likely Benign | 0.96 | Ambiguous | 1.30 | Destabilizing | 0.485 | Likely Benign | -4.39 | Deleterious | 0.877 | Possibly Damaging | 0.807 | Possibly Damaging | 4.15 | Benign | 0.27 | Tolerated | 3.38 | 28 | 0.1537 | 0.0957 | -1 | 0 | -6.4 | 24.99 | ||||||||||||||||||||||||||
| c.1418T>C | V473A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V473A missense variant is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are all uncertain or unavailable, providing no decisive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions support a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation (no contradiction). Thus, the variant is most likely pathogenic based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -10.867 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 1.88 | Ambiguous | 0.0 | 1.76 | Ambiguous | 1.82 | Ambiguous | 2.17 | Destabilizing | 0.485 | Likely Benign | -3.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.18 | Benign | 0.00 | Affected | 0.2529 | 0.2521 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1949A>T | N650I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N650I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX reports an uncertain outcome. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the balance of evidence favors 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 | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -15.940 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.50 | Ambiguous | 0.2 | 0.21 | Likely Benign | 0.36 | Likely Benign | 0.21 | Likely Benign | 0.485 | Likely Benign | -8.97 | Deleterious | 0.999 | Probably Damaging | 0.955 | Probably Damaging | 3.02 | Benign | 0.00 | Affected | 0.0907 | 0.4339 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.2089T>G | W697G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 W697G missense change 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. In contrast, a majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar). AlphaMissense‑Default and ESM1b are uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it receives one benign, one pathogenic, and two uncertain calls. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus remains unavailable. Overall, the preponderance of evidence from multiple independent pathogenicity predictors and the protein‑stability assessment by Foldetta indicates that W697G is most likely pathogenic. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.400169 | Uncertain | 0.945 | 0.297 | 0.000 | -7.429 | In-Between | 0.480 | Ambiguous | Likely Benign | 2.57 | Destabilizing | 0.1 | 2.38 | Destabilizing | 2.48 | Destabilizing | 1.21 | Destabilizing | 0.485 | Likely Benign | -8.93 | Deleterious | 1.000 | Probably Damaging | 0.987 | Probably Damaging | 3.44 | Benign | 0.06 | Tolerated | 0.3965 | 0.1482 | -7 | -2 | 0.5 | -129.16 | ||||||||||||||||||||||||||||||
| c.2099T>G | L700R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L700R 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 Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, 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 are mixed: AlphaMissense‑Optimized is inconclusive, SGM Consensus remains Likely Pathogenic, and Foldetta predicts a destabilizing, pathogenic effect. Overall, the preponderance 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 | GAP | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -12.389 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 1.82 | Ambiguous | 0.1 | 4.19 | Destabilizing | 3.01 | Destabilizing | 1.89 | Destabilizing | 0.485 | Likely Benign | -4.29 | Deleterious | 0.728 | Possibly Damaging | 0.249 | Benign | 3.35 | Benign | 0.01 | Affected | 0.1210 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.3608A>C | H1203P 2D AIThe SynGAP1 missense variant H1203P 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). AlphaMissense‑Optimized predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the balance of evidence (five pathogenic vs. four benign predictions) indicates that the variant is most likely pathogenic, 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. | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | -11.286 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.485 | Likely Benign | -2.10 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 5.47 | Benign | 0.26 | Tolerated | 0.1742 | 0.2820 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| 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.994G>T | D332Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D332Y 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. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, yields an uncertain result. Overall, the majority of evidence points to a pathogenic impact for D332Y, 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 | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -14.210 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | 1.15 | Ambiguous | 0.6 | -0.07 | Likely Benign | 0.54 | Ambiguous | 0.41 | Likely Benign | 0.485 | Likely Benign | -7.33 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.20 | Pathogenic | 0.00 | Affected | 0.0372 | 0.4018 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| 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.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.3473T>A | V1158D 2D AIThe SynGAP1 missense variant V1158D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence indicates that V1158D is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -4.076 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.486 | Likely Benign | -4.56 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.29 | Pathogenic | 0.00 | Affected | 0.1502 | 0.1820 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||||||||||||
| c.3578A>C | D1193A 2D AIThe SynGAP1 missense variant D1193A is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Based on the majority of predictions and the consensus from high‑accuracy tools, 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 | Coiled-coil | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | -5.747 | Likely Benign | 0.767 | Likely Pathogenic | Likely Benign | 0.486 | Likely Benign | -2.42 | Neutral | 0.856 | Possibly Damaging | 0.492 | Possibly Damaging | 5.48 | Benign | 0.00 | Affected | 0.2719 | 0.4017 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||
| 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.971G>C | R324P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, PROVEAN, and SIFT, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic” because three of the four contributing tools predict pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Based on the preponderance of pathogenic predictions—including the high‑accuracy tools—the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | -14.533 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.61 | Destabilizing | 0.5 | 2.19 | Destabilizing | 3.40 | Destabilizing | 1.03 | Destabilizing | 0.486 | Likely Benign | -2.15 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.83 | Pathogenic | 0.29 | Tolerated | 0.2291 | 0.5556 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1013A>G | D338G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D338G missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, premPS, and polyPhen‑2 HumVar. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Because the majority of available predictors (seven versus three) indicate a deleterious impact, 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 | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -8.875 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 1.33 | Ambiguous | 0.5 | 1.75 | Ambiguous | 1.54 | Ambiguous | 0.15 | Likely Benign | 0.487 | Likely Benign | -5.51 | Deleterious | 0.771 | Possibly Damaging | 0.315 | Benign | 1.69 | Pathogenic | 0.01 | Affected | 0.4014 | 0.5934 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| 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.1475A>G | K492R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K492R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools (seven pathogenic vs. six benign) lean toward a pathogenic interpretation, and this does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | -11.290 | Likely Pathogenic | 0.599 | Likely Pathogenic | Likely Benign | -0.20 | Likely Benign | 0.1 | 0.45 | Likely Benign | 0.13 | Likely Benign | 0.84 | Ambiguous | 0.487 | Likely Benign | -2.98 | Deleterious | 0.997 | Probably Damaging | 0.990 | Probably Damaging | 3.25 | Benign | 0.05 | Affected | 0.3911 | 0.0835 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.3566A>G | E1189G 2D AIThe SynGAP1 E1189G 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, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool reports an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic vs two benign votes). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of standard predictors (five pathogenic vs three benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -5.166 | Likely Benign | 0.904 | Likely Pathogenic | Ambiguous | 0.487 | Likely Benign | -3.47 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.26 | Benign | 0.05 | Affected | 0.2475 | 0.4030 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| 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.779T>C | V260A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260A 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, ESM1b, FATHMM, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote), and Foldetta. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools (premPS and AlphaMissense‑Default) give uncertain results. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta—all indicate a benign outcome. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.254060 | Structured | 0.382651 | Uncertain | 0.888 | 0.259 | 0.250 | -3.271 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.38 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.81 | Ambiguous | 0.487 | Likely Benign | -1.41 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.87 | Benign | 0.33 | Tolerated | 0.2676 | 0.1903 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.925G>A | G309S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include REVEL and SIFT, whereas a majority of other in silico predictors (AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SGM‑Consensus, and FoldX) predict it to be pathogenic. Tools with uncertain outcomes (Foldetta, Rosetta, premPS) provide no definitive 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, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that G309S is most likely pathogenic, 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 | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -11.335 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.5 | 0.73 | Ambiguous | 1.78 | Ambiguous | 0.72 | Ambiguous | 0.487 | Likely Benign | -5.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.73 | Pathogenic | 0.07 | Tolerated | 0.2828 | 0.5591 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1265A>G | E422G 2D 3DClick to see structure in 3D Viewer AISynGAP1 E422G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, premPS, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are provided by FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy analyses indicate that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts a likely pathogenic effect, whereas AlphaMissense‑Optimized remains inconclusive and Foldetta shows no definitive stability change. Overall, the majority of evidence points toward a pathogenic impact for E422G, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -11.468 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 1.13 | Ambiguous | 0.0 | 1.25 | Ambiguous | 1.19 | Ambiguous | 0.39 | Likely Benign | 0.488 | Likely Benign | -6.38 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.2440 | 0.4184 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1358A>C | H453P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H453P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM. The majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.352862 | Structured | 0.316097 | Uncertain | 0.946 | 0.200 | 0.000 | -15.704 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 3.29 | Destabilizing | 0.4 | 7.04 | Destabilizing | 5.17 | Destabilizing | 0.84 | Ambiguous | 0.488 | Likely Benign | -9.88 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.04 | Affected | 0.2115 | 0.3938 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1461C>G | N487K 2D AIThe SynGAP1 missense variant N487K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑related methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | 0.488 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1953 | 0.2721 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.962G>C | R321P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321P 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, 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 tools (8/12) predict pathogenicity, whereas 4/12 predict benign, with two high‑accuracy tools supporting benign and one supporting pathogenic. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict 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 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -11.576 | Likely Pathogenic | 0.740 | Likely Pathogenic | Likely Benign | 1.22 | Ambiguous | 0.3 | -0.77 | Ambiguous | 0.23 | Likely Benign | 0.41 | Likely Benign | 0.488 | Likely Benign | -3.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.92 | Pathogenic | 0.03 | Affected | 0.2186 | 0.3661 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.997A>G | K333E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K333E 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, and SIFT. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. 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 impact for K333E. 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 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -14.059 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.30 | Likely Benign | 0.12 | Likely Benign | 0.89 | Ambiguous | 0.488 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.91 | Pathogenic | 0.09 | Tolerated | 0.3429 | 0.1039 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1265A>T | E422V 2D 3DClick to see structure in 3D Viewer AISynGAP1 E422V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, Rosetta, Foldetta, premPS, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a likely pathogenic outcome, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign effect. FoldX remains uncertain. Overall, the majority of high‑confidence tools lean toward pathogenicity, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -12.371 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.90 | Ambiguous | 0.1 | -0.02 | Likely Benign | 0.44 | Likely Benign | 0.24 | Likely Benign | 0.489 | Likely Benign | -6.38 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.29 | Benign | 0.00 | Affected | 0.0609 | 0.5457 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1461C>A | N487K 2D AIThe SynGAP1 missense variant N487K 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 REVEL and FATHMM. The remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled “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 other stability predictions are available. 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 absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | 0.489 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1953 | 0.2721 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1678G>C | V560L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V560L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Optimized, and Foldetta; pathogenic predictions come from polyPhen‑2 HumDiv, ESM1b, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the bulk of evidence points to a benign effect, but the SGM Consensus and the presence of pathogenic signals from several high‑confidence tools introduce uncertainty. Thus, the variant is most likely benign based on the prevailing predictions, 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 | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | -10.191 | Likely Pathogenic | 0.533 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.0 | 0.48 | Likely Benign | 0.02 | Likely Benign | 0.45 | Likely Benign | 0.489 | Likely Benign | -2.45 | Neutral | 0.508 | Possibly Damaging | 0.209 | Benign | -1.24 | Pathogenic | 0.40 | Tolerated | 3.37 | 35 | 0.1430 | 0.4162 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||
| c.1678G>T | V560L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V560L variant has no ClinVar entry (ClinVar status: None) but is catalogued in gnomAD (ID 6‑33440730‑G‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, ESM1b, and FATHMM (polyPhen‑2 HumVar is benign, AlphaMissense‑Default is uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning pathogenic (2 pathogenic vs 1 benign), and Foldetta indicating a benign stability change. Overall, the majority of conventional tools favor a benign classification, yet the high‑accuracy consensus and Foldetta suggest a pathogenic signal. Based on the most reliable 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. | GAP | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | 6-33440730-G-T | 1 | 6.34e-7 | -10.191 | Likely Pathogenic | 0.533 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.0 | 0.48 | Likely Benign | 0.02 | Likely Benign | 0.45 | Likely Benign | 0.489 | Likely Benign | -2.45 | Neutral | 0.508 | Possibly Damaging | 0.209 | Benign | -1.24 | Pathogenic | 0.40 | Tolerated | 3.37 | 35 | 0.1430 | 0.4162 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.3673T>C | S1225P 2D AIThe SynGAP1 missense variant S1225P 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. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (five pathogenic vs. four benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -12.278 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.489 | Likely Benign | -2.07 | Neutral | 0.784 | Possibly Damaging | 0.575 | Possibly Damaging | 5.36 | Benign | 0.25 | Tolerated | 0.1499 | 0.4570 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.628C>G | H210D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210D 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, and FATHMM. In contrast, 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). Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and Rosetta alone is also uncertain. 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 H210D, 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 | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -16.440 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.13 | Likely Benign | 0.4 | 1.23 | Ambiguous | 0.68 | Ambiguous | 1.23 | Destabilizing | 0.489 | Likely Benign | -7.73 | Deleterious | 0.895 | Possibly Damaging | 0.533 | Possibly Damaging | 3.18 | Benign | 0.00 | Affected | 0.2025 | 0.1255 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.637A>C | I213L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all classify the variant as benign, while AlphaMissense‑Default predicts it as pathogenic and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a benign effect. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the collective evidence, and this benign prediction 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. | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -7.673 | In-Between | 0.577 | Likely Pathogenic | Likely Benign | 0.29 | Likely Benign | 0.4 | 0.20 | Likely Benign | 0.25 | Likely Benign | 0.45 | Likely Benign | 0.489 | Likely Benign | -1.45 | Neutral | 0.447 | Benign | 0.177 | Benign | 5.89 | Benign | 0.18 | Tolerated | 0.0771 | 0.2857 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.971G>T | R324L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324L is catalogued in gnomAD (6-33437876‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and SIFT; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome, and Foldetta (integrating FoldX‑MD and Rosetta outputs) reports a benign stability change. Overall, the majority of evidence points toward 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 Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | 6-33437876-G-T | 1 | 6.20e-7 | -10.328 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.28 | Likely Benign | 0.0 | -0.08 | Likely Benign | -0.18 | Likely Benign | 0.29 | Likely Benign | 0.489 | Likely Benign | -2.20 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.86 | Pathogenic | 0.63 | Tolerated | 3.39 | 22 | 0.2310 | 0.5607 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||
| c.1226T>A | M409K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M409K has no ClinVar record and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, SIFT, and FATHMM, while pathogenic calls arise from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also inconclusive. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.150080 | Structured | 0.360643 | Uncertain | 0.884 | 0.219 | 0.000 | -13.618 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.93 | Ambiguous | 0.3 | 0.29 | Likely Benign | 0.61 | Ambiguous | 1.45 | Destabilizing | 0.490 | Likely Benign | -4.26 | Deleterious | 0.769 | Possibly Damaging | 0.750 | Possibly Damaging | 4.18 | Benign | 0.40 | Tolerated | 0.1318 | 0.0656 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.1457A>T | E486V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E486V is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, SIFT, FATHMM, and Foldetta. Tools that predict a pathogenic effect comprise 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, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Uncertain results from FoldX and Rosetta are treated as unavailable. Overall, the majority of predictions support a pathogenic classification, and 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 | 0.196879 | Structured | 0.358545 | Uncertain | 0.833 | 0.245 | 0.125 | -15.115 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.54 | Ambiguous | 0.1 | -0.65 | Ambiguous | -0.06 | Likely Benign | 0.31 | Likely Benign | 0.490 | Likely Benign | -6.36 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 3.37 | Benign | 0.06 | Tolerated | 0.0493 | 0.6445 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1465C>A | L489I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; the remaining methods (FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is indeterminate due to a tie between pathogenic and benign signals, and Foldetta reports an uncertain stability change. Overall, the preponderance 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. | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -7.333 | In-Between | 0.342 | Ambiguous | Likely Benign | 1.01 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.77 | Ambiguous | 0.90 | Ambiguous | 0.490 | Likely Benign | -1.55 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.21 | Tolerated | 0.1069 | 0.4080 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.3527A>T | E1176V 2D AISynGAP1 missense variant E1176V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy consensus methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability approach, has no available result for this variant. Overall, the balance of evidence favors a benign classification, 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 Benign | Coiled-coil | 0.538167 | Disordered | 0.572075 | Binding | 0.525 | 0.715 | 0.250 | -3.238 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.490 | Likely Benign | -2.41 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 5.69 | Benign | 0.13 | Tolerated | 0.0452 | 0.6423 | -2 | -2 | 7.7 | -29.98 | ||||||||||||||||||||||||||||||||||||||
| c.3562G>T | D1188Y 2D AIThe SynGAP1 D1188Y 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, ESM1b, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evaluated tools (seven pathogenic versus three benign) indicate a pathogenic impact. This prediction aligns 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. | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -6.482 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.490 | Likely Benign | -4.49 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 5.40 | Benign | 0.00 | Affected | 0.0450 | 0.4714 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| 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.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.593T>C | L198P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198P has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions 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 show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a deleterious effect. Thus, 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 | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -12.250 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.55 | Ambiguous | 0.3 | 0.40 | Likely Benign | 0.98 | Ambiguous | 0.65 | Ambiguous | 0.491 | Likely Benign | -5.87 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.33 | Benign | 0.00 | Affected | 0.3882 | 0.1582 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||
| c.1568A>G | N523S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523S 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, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and FATHMM. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) returned uncertain or inconclusive results. For high‑accuracy assessment, AlphaMissense‑Optimized classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports an uncertain folding‑stability change. Taken together, the majority of evidence (five benign versus three pathogenic predictions) points to a benign effect, 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 | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -6.188 | Likely Benign | 0.552 | Ambiguous | Likely Benign | 0.64 | Ambiguous | 0.2 | 0.66 | Ambiguous | 0.65 | Ambiguous | 0.17 | Likely Benign | 0.492 | Likely Benign | -4.31 | Deleterious | 0.976 | Probably Damaging | 0.410 | Benign | -1.27 | Pathogenic | 0.27 | Tolerated | 0.2213 | 0.4178 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.1683C>A | F561L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the remaining tools (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome; FoldX is uncertain and therefore not counted as evidence. 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 also predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -8.947 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.2 | 2.52 | Destabilizing | 2.12 | Destabilizing | 1.39 | Destabilizing | 0.492 | Likely Benign | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -0.81 | Pathogenic | 0.32 | Tolerated | 0.1911 | 0.2629 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1886T>C | V629A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V629A 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, SIFT, and FATHMM. Those that predict a pathogenic effect comprise SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as Pathogenic (combining FoldX‑MD and Rosetta outputs). Overall, the majority of predictions (8 pathogenic vs. 3 benign) indicate that V629A is most likely pathogenic, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -8.652 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 2.24 | Destabilizing | 0.1 | 1.96 | Ambiguous | 2.10 | Destabilizing | 1.58 | Destabilizing | 0.492 | Likely Benign | -3.58 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.18 | Benign | 0.11 | Tolerated | 0.2518 | 0.2124 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.3566A>T | E1189V 2D AIThe SynGAP1 E1189V missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 vs 2). Foldetta stability predictions are not available. Overall, more tools (five) predict pathogenicity than benign (three), and the high‑accuracy methods do not overturn this trend. 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. | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -5.048 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.492 | Likely Benign | -3.50 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 5.26 | Benign | 0.02 | Affected | 0.0467 | 0.4252 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.1073T>C | F358S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F358S variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of algorithms predict a pathogenic outcome: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Rosetta’s assessment is uncertain and is not taken as evidence. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of pathogenic predictions and the agreement of the high‑accuracy tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.407113 | Uncertain | 0.912 | 0.441 | 0.250 | -9.316 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 2.32 | Destabilizing | 0.2 | 1.97 | Ambiguous | 2.15 | Destabilizing | 1.14 | Destabilizing | 0.493 | Likely Benign | -6.48 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 4.07 | Benign | 0.20 | Tolerated | 0.3891 | 0.1333 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.1190G>T | C397F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C397F is reported in gnomAD (6-33438095-G-T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, Rosetta, and the protein‑folding stability method Foldetta. FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as benign, while Foldetta indicates a pathogenic effect. Because the majority of tools (nine benign vs. four pathogenic) lean toward a benign outcome and the high‑accuracy consensus is split, the variant is most likely benign. This assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.395774 | Uncertain | 0.778 | 0.551 | 0.250 | 6-33438095-G-T | 1 | 6.20e-7 | -6.571 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 1.31 | Ambiguous | 1.7 | 3.61 | Destabilizing | 2.46 | Destabilizing | 0.12 | Likely Benign | 0.493 | Likely Benign | -1.95 | Neutral | 0.952 | Possibly Damaging | 0.497 | Possibly Damaging | 4.65 | Benign | 0.07 | Tolerated | 3.41 | 15 | 0.1426 | 0.5231 | -2 | -4 | 0.3 | 44.04 | ||||||||||||||||||||||||
| c.1292T>A | L431Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431Q resides in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic; this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -12.399 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.69 | Destabilizing | 0.0 | 2.37 | Destabilizing | 2.53 | Destabilizing | 1.99 | Destabilizing | 0.493 | Likely Benign | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.92 | Benign | 0.01 | Affected | 0.1036 | 0.1088 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1683C>G | F561L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the remaining tools (SGM‑Consensus, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome; FoldX is uncertain and therefore not counted as evidence. 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 also predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -8.947 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.2 | 2.52 | Destabilizing | 2.12 | Destabilizing | 1.39 | Destabilizing | 0.493 | Likely Benign | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -0.81 | Pathogenic | 0.32 | Tolerated | 0.1911 | 0.2629 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.3788T>G | I1263S 2D AIThe SynGAP1 missense variant I1263S 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 REVEL, whereas the remaining tools—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 predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled likely pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that 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 | Coiled-coil | 0.425610 | Structured | 0.740957 | Binding | 0.867 | 0.574 | 0.000 | -8.074 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.493 | Likely Benign | -4.97 | Deleterious | 0.984 | Probably Damaging | 0.825 | Possibly Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.3242 | 0.0910 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3888G>T | E1296D 2D AIThe SynGAP1 missense variant E1296D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence points to 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 | 0.837511 | Disordered | 0.894444 | Binding | 0.530 | 0.809 | 0.625 | -3.566 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.493 | Likely Benign | -2.15 | Neutral | 0.980 | Probably Damaging | 0.812 | Possibly Damaging | 2.59 | Benign | 0.04 | Affected | 0.1906 | 0.3443 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.878G>T | R293L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and premPS, while the remaining evaluated tools (SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict pathogenicity. Uncertain results from FoldX, Rosetta, and Foldetta are treated as unavailable. 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 pathogenic, and Foldetta provides no definitive stability change. Consequently, the variant is most likely pathogenic based on the consensus of predictive tools, 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 | C2 | 0.335645 | Structured | 0.338192 | Uncertain | 0.924 | 0.269 | 0.125 | -15.502 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.56 | Ambiguous | 0.2 | 0.93 | Ambiguous | 1.25 | Ambiguous | 0.08 | Likely Benign | 0.493 | Likely Benign | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.46 | Pathogenic | 0.01 | Affected | 0.1815 | 0.4987 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1256A>T | E419V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E419V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, FATHMM, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from the high‑accuracy tools contradicts the pathogenic prediction. Overall, the majority of computational evidence points to a pathogenic effect, which is consistent with the lack of ClinVar reporting and gnomAD absence, suggesting the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.371949 | Uncertain | 0.961 | 0.261 | 0.000 | -12.290 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.45 | Likely Benign | 0.0 | 1.41 | Ambiguous | 0.93 | Ambiguous | 0.27 | Likely Benign | 0.494 | Likely Benign | -6.55 | Deleterious | 0.998 | Probably Damaging | 0.983 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | 0.0953 | 0.6834 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1566A>C | E522D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522D missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and ESM1b, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a benign effect. Overall, the balance of evidence points to a likely pathogenic impact for E522D, 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 | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -5.385 | Likely Benign | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.04 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.01 | Likely Benign | 0.32 | Likely Benign | 0.494 | Likely Benign | -2.65 | Deleterious | 0.986 | Probably Damaging | 0.989 | Probably Damaging | -1.33 | Pathogenic | 0.10 | Tolerated | 0.1499 | 0.2765 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1566A>T | E522D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522D missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and ESM1b, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, indicates a benign effect. Overall, the balance of evidence points to a likely pathogenic impact for E522D, 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 | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -5.385 | Likely Benign | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.04 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.01 | Likely Benign | 0.32 | Likely Benign | 0.494 | Likely Benign | -2.65 | Deleterious | 0.986 | Probably Damaging | 0.989 | Probably Damaging | -1.33 | Pathogenic | 0.10 | Tolerated | 0.1499 | 0.2765 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| 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.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.1145G>C | G382A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 (HumDiv and 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, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of predictions lean toward a benign effect, and this consensus does not contradict any ClinVar status (none available). Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -6.323 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 2.90 | Destabilizing | 0.6 | 3.00 | Destabilizing | 2.95 | Destabilizing | -0.03 | Likely Benign | 0.495 | Likely Benign | -0.59 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.12 | Tolerated | 0.4048 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1595C>G | T532R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T532R missense variant is not listed in ClinVar and has no reported allele in gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, FATHMM, and AlphaMissense‑Default. FoldX and Rosetta provide uncertain results and are treated as unavailable. 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 effect. Overall, the balance of evidence (seven benign versus five pathogenic predictions) indicates that the variant is most likely benign, 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 | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -6.564 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | -0.57 | Ambiguous | 0.2 | 0.68 | Ambiguous | 0.06 | Likely Benign | 0.48 | Likely Benign | 0.495 | Likely Benign | -2.62 | Deleterious | 0.694 | Possibly Damaging | 0.230 | Benign | -1.20 | Pathogenic | 0.06 | Tolerated | 0.0841 | 0.1755 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||
| 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.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.3794G>T | R1265M 2D AIThe SynGAP1 missense variant R1265M is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that R1265M is most likely pathogenic, and 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. | Likely Pathogenic | Coiled-coil | 0.414856 | Structured | 0.782497 | Binding | 0.887 | 0.592 | 0.000 | -13.657 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.495 | Likely Benign | -4.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.25 | Pathogenic | 0.00 | Affected | 0.1442 | 0.4082 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||
| c.640C>G | L214V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L214V 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, premPS, and AlphaMissense‑Optimized—yield uncertain 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, PROVEAN), and Foldetta as uncertain. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -9.913 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 1.80 | Ambiguous | 0.4 | 0.54 | Ambiguous | 1.17 | Ambiguous | 0.89 | Ambiguous | 0.495 | Likely Benign | -2.54 | Deleterious | 0.384 | Benign | 0.070 | Benign | 5.78 | Benign | 0.01 | Affected | 0.1469 | 0.3887 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.961C>T | R321C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437866‑C‑T). Prediction tools that agree on a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Five tools (SGM‑Consensus, FoldX, Rosetta, AlphaMissense‑Default, and Foldetta) report uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (six out of eleven) support a pathogenic impact, while three support benign and five are inconclusive. Thus, the variant is most likely pathogenic based on current computational evidence, and this does not contradict its ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | Conflicting | 2 | 6-33437866-C-T | 9 | 5.58e-6 | -10.025 | Likely Pathogenic | 0.387 | Ambiguous | Likely Benign | 0.57 | Ambiguous | 0.1 | 0.56 | Ambiguous | 0.57 | Ambiguous | 0.18 | Likely Benign | 0.495 | Likely Benign | -4.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.89 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 0.3313 | 0.2516 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| c.1294T>A | C432S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C432S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools (SGM Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show SGM Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification for C432S, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -8.229 | Likely Pathogenic | 0.913 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.52 | Destabilizing | 0.496 | Likely Benign | -9.55 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.12 | Tolerated | 0.4262 | 0.1415 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1552T>C | Y518H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y518H is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and ESM1b. Predictions that are inconclusive are Foldetta, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for Y518H, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.126970 | Uncertain | 0.897 | 0.321 | 0.000 | Uncertain | 1 | -9.797 | Likely Pathogenic | 0.943 | Likely Pathogenic | Ambiguous | 2.39 | Destabilizing | 0.4 | 0.82 | Ambiguous | 1.61 | Ambiguous | 1.31 | Destabilizing | 0.496 | Likely Benign | -4.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.08 | Tolerated | 0.1927 | 0.0212 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||
| c.944A>T | N315I 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant N315I is not reported in ClinVar and is absent from gnomAD. In silico predictors that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, and AlphaMissense‑Optimized. Predictors that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD (uncertain) and Rosetta (benign), is considered unavailable. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -9.666 | Likely Pathogenic | 0.500 | Ambiguous | Likely Benign | -0.72 | Ambiguous | 0.4 | -0.17 | Likely Benign | -0.45 | Likely Benign | 0.36 | Likely Benign | 0.496 | Likely Benign | -5.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.43 | Tolerated | 0.0763 | 0.7235 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.970C>G | R324G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324G 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 AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With the majority of evidence pointing to deleterious impact and two of the three high‑accuracy methods supporting pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | -12.266 | Likely Pathogenic | 0.708 | Likely Pathogenic | Likely Benign | 2.99 | Destabilizing | 0.1 | 3.18 | Destabilizing | 3.09 | Destabilizing | 1.27 | Destabilizing | 0.496 | Likely Benign | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.84 | Pathogenic | 0.39 | Tolerated | 0.3546 | 0.4135 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1123G>A | G375R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G375R is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas tools that predict pathogenicity are FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of predictions (7 pathogenic vs. 5 benign) indicate a likely pathogenic effect, 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 Pathogenic | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -8.955 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | 2.97 | Destabilizing | 1.3 | 12.66 | Destabilizing | 7.82 | Destabilizing | 0.36 | Likely Benign | 0.497 | Likely Benign | -1.15 | Neutral | 0.845 | Possibly Damaging | 0.523 | Possibly Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.1335 | 0.4513 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1123G>C | G375R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts benign, whereas Foldetta indicates a destabilizing, pathogenic change, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as likely pathogenic. Overall, the majority of evidence points to 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 | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -8.955 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | 2.97 | Destabilizing | 1.3 | 12.66 | Destabilizing | 7.82 | Destabilizing | 0.36 | Likely Benign | 0.497 | Likely Benign | -1.15 | Neutral | 0.845 | Possibly Damaging | 0.523 | Possibly Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.1335 | 0.4513 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1133G>C | G378A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as “Likely Benign.” High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a benign likelihood, while Foldetta—combining FoldX‑MD and Rosetta outputs—predicts a pathogenic effect on protein folding stability. Overall, the majority of evidence points toward a benign impact, and this conclusion is consistent with the absence of ClinVar annotation and gnomAD data. Thus, 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 | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -6.450 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 5.06 | Destabilizing | 1.3 | 6.00 | Destabilizing | 5.53 | Destabilizing | -0.04 | Likely Benign | 0.497 | Likely Benign | -0.55 | Neutral | 0.999 | Probably Damaging | 0.981 | Probably Damaging | 1.33 | Pathogenic | 0.18 | Tolerated | 0.4062 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| 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.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.1462A>G | T488A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T488A is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while the majority of tools (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus) predict pathogenicity; Rosetta and premPS are uncertain. 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, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the preponderance of evidence indicates that T488A 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 | 0.206376 | Structured | 0.332663 | Uncertain | 0.928 | 0.233 | 0.125 | -11.341 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.2 | 1.99 | Ambiguous | 2.06 | Destabilizing | 0.57 | Ambiguous | 0.497 | Likely Benign | -4.64 | Deleterious | 0.996 | Probably Damaging | 0.989 | Probably Damaging | 3.24 | Benign | 0.01 | Affected | 0.2871 | 0.2872 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| c.1622C>T | A541V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A541V is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, Foldetta, premPS, SIFT, Rosetta, and AlphaMissense‑Optimized, whereas pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, polyPhen2_HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy tools give mixed results: AlphaMissense‑Optimized predicts benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. FoldX is uncertain and therefore not considered. Overall, the majority of tools predict pathogenicity, and this assessment 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 | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -9.777 | Likely Pathogenic | 0.762 | Likely Pathogenic | Likely Benign | 0.63 | Ambiguous | 0.1 | 0.06 | Likely Benign | 0.35 | Likely Benign | 0.43 | Likely Benign | 0.497 | Likely Benign | -3.09 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | -1.33 | Pathogenic | 0.06 | Tolerated | 0.0985 | 0.3648 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.2035T>G | F679V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious effect: the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic, while AlphaMissense‑Optimized and Foldetta provide inconclusive results and are treated as unavailable. Overall, the balance of evidence favors a pathogenic classification, 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 | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -11.868 | Likely Pathogenic | 0.900 | Likely Pathogenic | Ambiguous | 1.92 | Ambiguous | 0.5 | 0.29 | Likely Benign | 1.11 | Ambiguous | 0.89 | Ambiguous | 0.497 | Likely Benign | -6.86 | Deleterious | 0.993 | Probably Damaging | 0.968 | Probably Damaging | 3.50 | Benign | 0.01 | Affected | 0.1830 | 0.2349 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.2789C>A | P930H 2D AIThe SynGAP1 missense variant P930H 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 REVEL, which scores the variant as benign. All other evaluated predictors—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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, reports the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence from multiple independent predictors and high‑accuracy tools indicates that P930H is most likely pathogenic, 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 Pathogenic | 0.538167 | Disordered | 0.988036 | Binding | 0.304 | 0.855 | 0.375 | -9.824 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 0.497 | Likely Benign | -6.44 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.65 | Pathogenic | 0.00 | Affected | 0.1942 | 0.4392 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3151G>T | G1051C 2D AIThe SynGAP1 missense variant G1051C is listed in ClinVar as Pathogenic and is not reported in gnomAD. Functional prediction tools show a split assessment: benign calls come from REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. High‑accuracy methods give a benign result from AlphaMissense‑Optimized; the SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is tied (2 benign vs. 2 pathogenic) and therefore inconclusive, and Foldetta’s stability prediction is unavailable. Overall, the majority of predictions lean toward a benign effect, which contradicts the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | Likely Pathogenic | 1 | -9.050 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | 0.497 | Likely Benign | -0.90 | Neutral | 0.971 | Probably Damaging | 0.750 | Possibly Damaging | -0.74 | Pathogenic | 0.10 | Tolerated | 3.77 | 5 | 0.1322 | 0.4612 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||
| c.3154G>A | G1052R 2D AISynGAP1 missense variant G1052R is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, which does not contradict the ClinVar uncertain status but provides additional support toward a likely benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | Uncertain | 1 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0976 | 0.4142 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||
| c.3154G>C | G1052R 2D AIThe SynGAP1 missense variant G1052R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and ESM1b predict a pathogenic outcome; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, 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. | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -9.050 | Likely Pathogenic | 0.383 | Ambiguous | Likely Benign | 0.497 | Likely Benign | -0.41 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 3.90 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0976 | 0.4142 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3491T>A | L1164Q 2D AIThe SynGAP1 missense variant L1164Q has no ClinVar record and is not present in gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.853935 | Binding | 0.325 | 0.815 | 0.375 | -5.374 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.497 | Likely Benign | -0.95 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 5.32 | Benign | 0.18 | Tolerated | 0.1171 | 0.1181 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.878G>C | R293P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R293P is listed in ClinVar as Pathogenic (ClinVar ID 571092.0) and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL and premPS, whereas the remaining tools—FoldX, Rosetta, Foldetta, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as Pathogenic; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies it as Pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is concordant with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.338192 | Uncertain | 0.924 | 0.269 | 0.125 | Likely Pathogenic | 1 | -16.275 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.62 | Destabilizing | 0.4 | 9.06 | Destabilizing | 6.34 | Destabilizing | 0.47 | Likely Benign | 0.497 | Likely Benign | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.45 | Pathogenic | 0.01 | Affected | 3.38 | 23 | 0.2162 | 0.4778 | 0 | -2 | 2.9 | -59.07 | 202.3 | 132.0 | 0.1 | 0.0 | 0.1 | 0.1 | X | X | X | Potentially Pathogenic | The guanidinium group of the Arg293 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), packs against the phenol ring of the Tyr281 side chain or forms a salt bridge with the carboxylate group of Glu283 on the outer side of the C2 domain. In the WT simulations, the positively charged side chain of arginine remains outside the hydrophobic C2 domain, resulting in a twist in the β strand. The backbone amide bond of Arg293 potentially maintains this twist by forming a hydrogen bond with the carbonyl group of His210 or the hydroxyl group of Ser211 in the anti-parallel β sheet.Although this twist is also maintained in the variant simulations, replacing the positively charged residue with proline, which lacks the backbone amide group altogether, causes the β strand to unfold. Because Arg293 is positioned at the C2 and PH domain interface, the residue swap could significantly impact the tertiary structure assembly. Notably, Arg293 is located at the SynGAP-Ras interface, and its role in complex formation cannot be fully understood through solvent-only simulations. | ||||||||||||||
| c.1195G>C | A399P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A399P 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, PROVEAN, SIFT, FATHMM, and polyPhen‑2 HumVar; pathogenic predictions come from FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta predicts a pathogenic effect. Overall, the majority of evidence points toward a deleterious impact. 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. | C2 | 0.394753 | Structured | 0.407674 | Uncertain | 0.939 | 0.490 | 0.125 | -8.809 | Likely Pathogenic | 0.942 | Likely Pathogenic | Ambiguous | 2.29 | Destabilizing | 0.1 | 4.00 | Destabilizing | 3.15 | Destabilizing | 0.74 | Ambiguous | 0.498 | Likely Benign | -1.82 | Neutral | 0.596 | Possibly Damaging | 0.188 | Benign | 5.56 | Benign | 0.10 | Tolerated | 0.1847 | 0.5472 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| 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.1675T>C | C559R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C559R 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, FATHMM, Rosetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools (six pathogenic vs five benign) lean toward a pathogenic interpretation, and this does not contradict any ClinVar status because the variant is not yet classified in ClinVar. 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. | Likely Pathogenic | GAP | 0.016021 | Structured | 0.010460 | Uncertain | 0.842 | 0.204 | 0.000 | -9.509 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | -1.03 | Ambiguous | 0.1 | -0.38 | Likely Benign | -0.71 | Ambiguous | 0.79 | Ambiguous | 0.498 | Likely Benign | -8.58 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.48 | Benign | 0.46 | Tolerated | 0.2498 | 0.1720 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.2035T>A | F679I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F679I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM. In contrast, a majority of predictors—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently classify the substitution as pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as Likely Pathogenic. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains pathogenic. Because the uncertain results are treated as unavailable, the clear majority of predictions support pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for F679I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.129316 | Uncertain | 0.700 | 0.320 | 0.000 | -12.620 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.62 | Ambiguous | 0.4 | -0.27 | Likely Benign | 0.68 | Ambiguous | 0.88 | Ambiguous | 0.498 | Likely Benign | -5.91 | Deleterious | 0.993 | Probably Damaging | 0.977 | Probably Damaging | 3.59 | Benign | 0.01 | Affected | 0.1725 | 0.2322 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.3142G>T | G1048W 2D AIThe SynGAP1 missense variant G1048W 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, FATHMM, 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, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -8.803 | Likely Pathogenic | 0.340 | Likely Benign | Likely Benign | 0.498 | Likely Benign | -1.52 | Neutral | 0.996 | Probably Damaging | 0.961 | Probably Damaging | 2.54 | Benign | 0.02 | Affected | 0.0852 | 0.4046 | -7 | -2 | -0.5 | 129.16 | |||||||||||||||||||||||||||||||||||||||
| c.811G>A | A271T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only REVEL, whereas the remaining evidence—premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—consistently predict pathogenicity. FoldX, Rosetta, and Foldetta are inconclusive, and AlphaMissense‑Optimized also yields an uncertain result. High‑accuracy assessments show that the SGM‑Consensus (majority vote) predicts pathogenicity, while AlphaMissense‑Optimized and Foldetta remain unavailable. Taken together, the overwhelming majority of reliable predictors classify the variant as pathogenic, and this conclusion does not conflict with the ClinVar status, which currently has no entry for A271T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | -9.564 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.59 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.57 | Ambiguous | 1.00 | Destabilizing | 0.498 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 0.66 | Pathogenic | 0.01 | Affected | 0.1076 | 0.4691 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.827C>G | P276R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P276R missense variant is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID 6‑33437732‑C‑G). Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Stability‑based predictors (FoldX, Rosetta, premPS, Foldetta) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic classification; this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.037156 | Structured | 0.338937 | Uncertain | 0.724 | 0.230 | 0.250 | 6-33437732-C-G | 7 | 4.34e-6 | -10.983 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 1.78 | Ambiguous | 0.2 | 1.02 | Ambiguous | 1.40 | Ambiguous | 0.78 | Ambiguous | 0.498 | Likely Benign | -4.52 | Deleterious | 0.994 | Probably Damaging | 0.892 | Possibly Damaging | 1.89 | Pathogenic | 0.01 | Affected | 3.38 | 19 | 0.1445 | 0.2828 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||
| 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.1643A>C | E548A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E548A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, FATHMM, premPS, and Foldetta, whereas pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic call from AlphaMissense‑Optimized, a likely pathogenic verdict from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and a benign result from Foldetta. Overall, the majority of evidence points to a pathogenic effect, so 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 | 0.054297 | Structured | 0.008632 | Uncertain | 0.965 | 0.288 | 0.000 | -13.543 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 0.56 | Ambiguous | 0.37 | Likely Benign | 0.48 | Likely Benign | 0.499 | Likely Benign | -5.83 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.05 | Affected | 0.3035 | 0.4328 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1915T>C | F639L 2D AIThe SynGAP1 missense variant F639L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen2_HumVar, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, FoldX, premPS, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta and Foldetta provide uncertain results. High‑accuracy assessments indicate that AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. Based on the majority of predictions, the variant is most likely pathogenic, which is consistent with the lack of ClinVar annotation and gnomAD absence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -11.660 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.7 | 1.15 | Ambiguous | 1.64 | Ambiguous | 1.43 | Destabilizing | 0.499 | Likely Benign | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.380 | Benign | 3.12 | Benign | 0.03 | Affected | 0.2347 | 0.2726 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| 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.2158G>T | D720Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D720Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and premPS, while pathogenic predictions are made by SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Predictions from FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized are inconclusive. The high‑accuracy consensus (SGM Consensus) classifies the variant as Likely Pathogenic, and Foldetta likewise yields an uncertain stability change. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of evidence points to a pathogenic effect, and this assessment 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 | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -14.771 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | -0.74 | Ambiguous | 0.1 | -1.38 | Ambiguous | -1.06 | Ambiguous | 0.20 | Likely Benign | 0.499 | Likely Benign | -7.05 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.11 | Pathogenic | 0.00 | Affected | 0.0626 | 0.5973 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.3584T>A | V1195E 2D AIThe SynGAP1 missense variant V1195E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. AlphaMissense‑Optimized yields an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the balance of evidence leans toward a benign impact, with no conflict with ClinVar status (which has no entry). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -1.722 | Likely Benign | 0.946 | Likely Pathogenic | Ambiguous | 0.499 | Likely Benign | -2.19 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.64 | Benign | 0.02 | Affected | 0.0870 | 0.1268 | -2 | -2 | -7.7 | 29.98 | ||||||||||||||||||||||||||||||||||||||
| c.854G>C | C285S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and SIFT, whereas premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. Predictions from FoldX, Rosetta, ESM1b, AlphaMissense‑Optimized, and Foldetta are inconclusive. 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, reports a likely pathogenic classification; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for C285S, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.149 | In-Between | 0.868 | Likely Pathogenic | Ambiguous | 0.73 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.74 | Ambiguous | 1.20 | Destabilizing | 0.499 | Likely Benign | -8.09 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.90 | Pathogenic | 0.08 | Tolerated | 0.5210 | 0.2038 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| c.1259T>G | F420C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F420C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. When grouped by consensus, the benign prediction is singular (FATHMM), whereas the pathogenic predictions comprise the remaining eleven tools. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.384475 | Uncertain | 0.974 | 0.255 | 0.000 | -11.931 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.31 | Destabilizing | 0.1 | 5.11 | Destabilizing | 4.71 | Destabilizing | 2.49 | Destabilizing | 0.500 | Likely Pathogenic | -7.40 | Deleterious | 0.998 | Probably Damaging | 0.869 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.2458 | 0.0662 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1603A>T | S535C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S535C 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 Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM. Two tools, FoldX and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of predictions lean toward a benign effect, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | -7.526 | In-Between | 0.165 | Likely Benign | Likely Benign | 0.57 | Ambiguous | 0.1 | 0.25 | Likely Benign | 0.41 | Likely Benign | 0.47 | Likely Benign | 0.500 | Likely Pathogenic | -2.96 | Deleterious | 0.933 | Possibly Damaging | 0.419 | Benign | -1.33 | Pathogenic | 0.02 | Affected | 0.1139 | 0.5633 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.1621G>A | A541T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A541T missense variant is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that report a benign effect include Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools (FoldX and AlphaMissense‑Default) returned uncertain results. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leans pathogenic. Overall, the majority of tools (six benign vs. five pathogenic) suggest a benign impact, 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. | GAP | 0.050641 | Structured | 0.029947 | Uncertain | 0.955 | 0.365 | 0.000 | -8.555 | Likely Pathogenic | 0.541 | Ambiguous | Likely Benign | 0.52 | Ambiguous | 0.0 | -0.07 | Likely Benign | 0.23 | Likely Benign | 0.45 | Likely Benign | 0.500 | Likely Pathogenic | -2.02 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.28 | Pathogenic | 0.15 | Tolerated | 0.1088 | 0.4164 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.3668T>C | L1223P 2D AIThe SynGAP1 missense variant L1223P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, 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. 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 confirm this: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus agrees. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the concordant pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.608892 | Disordered | 0.436267 | Uncertain | 0.868 | 0.540 | 0.375 | -14.728 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.500 | Likely Pathogenic | -5.17 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 1.45 | Pathogenic | 0.01 | Affected | 0.3413 | 0.2352 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| c.854G>T | C285F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; Foldetta is uncertain. 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 preponderance of evidence (12 pathogenic vs. 3 benign predictions) indicates 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 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -9.397 | Likely Pathogenic | 0.716 | Likely Pathogenic | Likely Benign | 3.27 | Destabilizing | 1.1 | -1.72 | Ambiguous | 0.78 | Ambiguous | 0.35 | Likely Benign | 0.500 | Likely Pathogenic | -8.84 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.81 | Pathogenic | 0.12 | Tolerated | 0.1626 | 0.4007 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1021G>T | G341C 2D AIThe SynGAP1 missense variant G341C has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (likely benign). Tools that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; Rosetta remains 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 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 Benign | C2 | 0.356642 | Structured | 0.431164 | Uncertain | 0.745 | 0.479 | 0.250 | -6.156 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.42 | Likely Benign | 1.2 | -0.92 | Ambiguous | -0.25 | Likely Benign | 0.24 | Likely Benign | 0.501 | Likely Pathogenic | -2.40 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 0.34 | Pathogenic | 0.01 | Affected | 0.1285 | 0.3650 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1267T>A | Y423N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y423N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include SIFT and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the overwhelming majority of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.088832 | Structured | 0.421885 | Uncertain | 0.975 | 0.242 | 0.000 | -10.937 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.1 | 4.08 | Destabilizing | 4.03 | Destabilizing | 2.07 | Destabilizing | 0.501 | Likely Pathogenic | -7.47 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.40 | Benign | 0.06 | Tolerated | 0.1405 | 0.0412 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1906T>A | F636I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F636I 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) reports pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among both general and high‑accuracy tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status 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 | 0.041405 | Structured | 0.071525 | Uncertain | 0.913 | 0.264 | 0.000 | -14.031 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.96 | Destabilizing | 0.2 | 4.57 | Destabilizing | 3.77 | Destabilizing | 1.10 | Destabilizing | 0.501 | Likely Pathogenic | -5.78 | Deleterious | 0.994 | Probably Damaging | 0.977 | Probably Damaging | 3.44 | Benign | 0.03 | Affected | 0.1660 | 0.2153 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.2774T>C | L925P 2D AIThe SynGAP1 missense variant L925P 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 ESM1b, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from multiple in silico predictors indicates that the variant is most likely pathogenic, 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 Pathogenic | 0.483068 | Structured | 0.977963 | Binding | 0.290 | 0.852 | 0.125 | -2.733 | Likely Benign | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.501 | Likely Pathogenic | -5.12 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.3083 | 0.1996 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| 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.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.3610T>C | S1204P 2D AIThe SynGAP1 missense variant S1204P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S1204P. This prediction 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. | Coiled-coil | 0.595080 | Disordered | 0.541098 | Binding | 0.887 | 0.587 | 0.375 | -14.031 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.502 | Likely Pathogenic | -1.80 | Neutral | 0.988 | Probably Damaging | 0.856 | Possibly Damaging | 5.39 | Benign | 0.31 | Tolerated | 0.2139 | 0.3886 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.1231A>T | I411F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411F is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -13.377 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 5.71 | Destabilizing | 0.1 | 4.53 | Destabilizing | 5.12 | Destabilizing | 0.73 | Ambiguous | 0.503 | Likely Pathogenic | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.973 | Probably Damaging | 3.30 | Benign | 0.00 | Affected | 0.0538 | 0.2853 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1235T>G | L412W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412W is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -13.436 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 8.44 | Destabilizing | 0.4 | 9.91 | Destabilizing | 9.18 | Destabilizing | 1.65 | Destabilizing | 0.503 | Likely Pathogenic | -5.53 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.19 | Benign | 0.00 | Affected | 0.0586 | 0.2664 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||
| c.1241T>A | M414K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M414K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. FoldX and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is unavailable. Based on the overwhelming agreement among the majority of prediction tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.329108 | Uncertain | 0.914 | 0.217 | 0.000 | -13.537 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.18 | Ambiguous | 0.1 | 2.39 | Destabilizing | 1.79 | Ambiguous | 1.50 | Destabilizing | 0.503 | Likely Pathogenic | -5.03 | Deleterious | 0.942 | Possibly Damaging | 0.860 | Possibly Damaging | 3.40 | Benign | 0.04 | Affected | 0.1299 | 0.0888 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
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