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.501C>G | D167E 2D  AIThe SynGAP1 D167E 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, 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 AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it receives two benign votes and two uncertain votes, yielding no clear majority. Foldetta, which would provide a protein‑folding stability estimate, 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 (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -7.636 | In-Between | 0.516 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.52 | Neutral | 0.063 | Benign | 0.062 | Benign | 4.07 | Benign | 0.00 | Affected | 0.1392 | 0.7144 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.505G>C | D169H 2D  AIThe SynGAP1 D169H 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 effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the majority of computational evidence points toward a pathogenic impact, 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 | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -12.048 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -2.83 | Deleterious | 0.651 | Possibly Damaging | 0.417 | Benign | 4.03 | Benign | 0.00 | Affected | 0.1791 | 0.7624 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.505G>T | D169Y 2D  AIThe SynGAP1 missense variant D169Y 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 effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized returns an uncertain result, and no Foldetta (FoldX‑MD/Rosetta) stability data are available. Based on the overall pattern of predictions, 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. | Likely Pathogenic | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -13.524 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.282 | Likely Benign | -3.71 | Deleterious | 0.651 | Possibly Damaging | 0.347 | Benign | 4.01 | Benign | 0.00 | Affected | 0.0571 | 0.6896 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.506A>T | D169V 2D  AIThe SynGAP1 D169V missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. When predictions are grouped by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, whereas 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 balance of evidence, particularly the SGM Consensus and the pathogenic calls from multiple independent predictors, indicates that D169V 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 | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -12.395 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.243 | Likely Benign | -3.77 | Deleterious | 0.380 | Benign | 0.193 | Benign | 4.03 | Benign | 0.00 | Affected | 0.0895 | 0.7166 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||||||||||||
| c.508C>G | R170G 2D  AIThe SynGAP1 missense variant R170G is not reported in ClinVar and has no entries in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, 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—classifies the variant as 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 impact for R170G, 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 | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -10.092 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -3.19 | Deleterious | 0.664 | Possibly Damaging | 0.137 | Benign | 3.88 | Benign | 0.00 | Affected | 0.3285 | 0.3004 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.508C>T | R170W 2D  AIThe SynGAP1 missense variant R170W is listed in ClinVar (ID 1310195.0) with an “Uncertain” status and is not reported in gnomAD. 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 outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus indicates it is likely pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect, 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 | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | Uncertain | 2 | -11.660 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.241 | Likely Benign | -4.28 | Deleterious | 0.999 | Probably Damaging | 0.849 | Possibly Damaging | 3.84 | Benign | 0.00 | Affected | 3.74 | 4 | 0.1026 | 0.3469 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||
| c.509G>A | R170Q 2D  AISynGAP1 missense variant R170Q is listed in ClinVar as Pathogenic and is not reported in gnomAD. Computational predictors show a split: benign calls come from REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive; Foldetta stability analysis is unavailable. Thus, no single method or high‑accuracy consensus strongly supports pathogenicity. The variant is most likely benign according to the current computational evidence, which contradicts the ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | Pathogenic/Likely path. | 6 | -9.021 | Likely Pathogenic | 0.798 | Likely Pathogenic | Ambiguous | 0.221 | Likely Benign | -2.31 | Neutral | 0.947 | Possibly Damaging | 0.342 | Benign | 3.91 | Benign | 0.00 | Affected | 3.74 | 4 | 0.2524 | 0.2299 | 1 | 1 | 1.0 | -28.06 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||||
| c.509G>C | R170P 2D  AIThe SynGAP1 missense variant R170P 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 score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 preponderance of evidence from both general and high‑accuracy predictors indicates that R170P 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 | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -9.687 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.386 | Likely Benign | -3.96 | Deleterious | 0.966 | Probably Damaging | 0.599 | Possibly Damaging | 3.86 | Benign | 0.00 | Affected | 0.1967 | 0.3989 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.509G>T | R170L 2D  AIThe SynGAP1 missense variant R170L has no ClinVar entry and is not reported in gnomAD. In silico predictors fall into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy tools further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) 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 preponderance of pathogenic predictions, including the high‑accuracy consensus, suggests that R170L is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.480142 | Structured | 0.492928 | Uncertain | 0.406 | 0.661 | 0.250 | -8.649 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.319 | Likely Benign | -4.02 | Deleterious | 0.798 | Possibly Damaging | 0.319 | Benign | 3.87 | Benign | 0.00 | Affected | 0.1561 | 0.4310 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.50C>A | S17Y 2D  AIThe SynGAP1 missense variant S17Y is listed in gnomAD (ID 6‑33420314‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign trend: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. No Foldetta stability data are available, so it does not influence the conclusion. Overall, the majority of evidence indicates that S17Y is most likely benign, and this assessment does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | 6-33420314-C-A | -4.492 | Likely Benign | 0.551 | Ambiguous | Likely Benign | 0.050 | Likely Benign | -1.06 | Neutral | 0.742 | Possibly Damaging | 0.047 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0818 | 0.6366 | -2 | -3 | -0.5 | 76.10 | ||||||||||||||||||||||||||||||||||||
| c.50C>G | S17C 2D  AIThe SynGAP1 missense variant S17C 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. 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 reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; 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 | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -4.364 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.044 | Likely Benign | 0.17 | Neutral | 0.486 | Possibly Damaging | 0.048 | Benign | 3.99 | Benign | 0.00 | Affected | 0.1226 | 0.6721 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.50C>T | S17F 2D  AIThe SynGAP1 missense variant S17F is listed in ClinVar (ID 3451958) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33420314‑C‑T). 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, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign 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 “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | Conflicting | 2 | 6-33420314-C-T | 10 | 6.49e-6 | -3.888 | Likely Benign | 0.637 | Likely Pathogenic | Likely Benign | 0.048 | Likely Benign | -0.99 | Neutral | 0.486 | Possibly Damaging | 0.032 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0729 | 0.6468 | -2 | -3 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||
| c.514C>T | R172W 2D AIThe SynGAP1 missense variant R172W is listed in ClinVar (ID 996892.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33435156‑C‑T). Prediction tools that agree on a benign effect include REVEL and FATHMM. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic.” AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. High‑accuracy assessments therefore indicate a likely pathogenic outcome (SGM‑Consensus) with no definitive stabilizing‑folding evidence. Overall, the majority of computational predictions support a pathogenic classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.525368 | Disordered | 0.491688 | Uncertain | 0.411 | 0.651 | 0.375 | Uncertain | 2 | 6-33435156-C-T | 9 | 5.58e-6 | -10.258 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 0.228 | Likely Benign | -3.61 | Deleterious | 0.997 | Probably Damaging | 0.803 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1071 | 0.4065 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.52T>A | Y18N 2D  AIThe SynGAP1 missense variant Y18N is listed in gnomAD (ID 6‑33420316‑T‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. 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 any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | 6-33420316-T-A | -3.094 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.075 | Likely Benign | -0.73 | Neutral | 0.872 | Possibly Damaging | 0.114 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2564 | 0.1253 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||
| c.52T>C | Y18H 2D  AIThe SynGAP1 missense variant Y18H is listed in gnomAD (ID 6‑33420316‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, 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 points to a benign impact, and this conclusion 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 | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | 6-33420316-T-C | -2.871 | Likely Benign | 0.542 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.58 | Neutral | 0.872 | Possibly Damaging | 0.114 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2805 | 0.0993 | 2 | 0 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||||
| c.52T>G | Y18D 2D  AIThe SynGAP1 missense variant Y18D is not 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, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, 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 Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the computational evidence overwhelmingly suggests that Y18D is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | -2.783 | Likely Benign | 0.580 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -0.44 | Neutral | 0.659 | Possibly Damaging | 0.072 | Benign | 4.06 | Benign | 0.00 | Affected | 0.4207 | 0.1253 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||||||||||||
| c.533A>T | K178M 2D  AIThe SynGAP1 missense variant K178M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). 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 or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: 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 any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | -13.585 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | -3.95 | Deleterious | 0.992 | Probably Damaging | 0.751 | Possibly Damaging | 3.83 | Benign | 0.00 | Affected | 0.1486 | 0.3607 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||||||||||||
| c.539C>T | S180L 2D  AIThe SynGAP1 missense variant S180L 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 effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM‑Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a “Likely Pathogenic” classification. AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic 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 Pathogenic | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -12.967 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.250 | Likely Benign | -3.80 | Deleterious | 0.608 | Possibly Damaging | 0.202 | Benign | 3.84 | Benign | 0.00 | Affected | 0.0885 | 0.5550 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.53A>C | Y18S 2D  AIThe SynGAP1 missense variant Y18S is reported in gnomAD (ID 6‑33420317‑A‑C) but has no ClinVar entry. 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 only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign impact for Y18S. This conclusion is consistent with the absence of a pathogenic ClinVar classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | 6-33420317-A-C | -1.061 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -0.50 | Neutral | 0.389 | Benign | 0.036 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4961 | 0.2640 | -2 | -3 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||||||||
| c.53A>G | Y18C 2D  AIThe SynGAP1 missense variant Y18C is listed in ClinVar (ID 1967233) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33420317‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome, and AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign 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 | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | Uncertain | 2 | 6-33420317-A-G | 44 | 2.88e-5 | -2.658 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.56 | Neutral | 0.872 | Possibly Damaging | 0.206 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3293 | 0.2473 | 0 | -2 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||
| c.53A>T | Y18F 2D  AIThe SynGAP1 missense variant Y18F 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. 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 | 0.483068 | Structured | 0.446314 | Uncertain | 0.345 | 0.908 | 0.375 | -2.371 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.19 | Neutral | 0.115 | Benign | 0.018 | Benign | 4.18 | Benign | 0.00 | Affected | 0.2675 | 0.3322 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.544T>A | S182T 2D  AIThe SynGAP1 missense variant S182T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of available predictions (five benign vs three pathogenic) suggest a benign impact. This consensus does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Thus, based on current computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -11.247 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.128 | Likely Benign | -2.29 | Neutral | 0.231 | Benign | 0.081 | Benign | 3.68 | Benign | 0.00 | Affected | 0.1624 | 0.5657 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.544T>C | S182P 2D  AIThe SynGAP1 missense variant S182P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by 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 pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple independent predictors 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 | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -13.362 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.279 | Likely Benign | -3.71 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.67 | Benign | 0.00 | Affected | 0.2438 | 0.5030 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.544T>G | S182A 2D  AIThe SynGAP1 missense variant S182A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of standard predictors lean toward a benign impact, and no ClinVar evidence contradicts this assessment. 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. | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -9.417 | Likely Pathogenic | 0.838 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | -2.26 | Neutral | 0.001 | Benign | 0.005 | Benign | 3.70 | Benign | 0.00 | Affected | 0.5466 | 0.4660 | Weaken | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||||||||||||
| c.545C>A | S182Y 2D AIThe SynGAP1 missense variant S182Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign calls are made only by REVEL and FATHMM. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized indicates a pathogenic effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic. A protein‑folding stability analysis with Foldetta is unavailable, so it does 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 | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -15.951 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | -4.40 | Deleterious | 0.940 | Possibly Damaging | 0.564 | Possibly Damaging | 3.64 | Benign | 0.00 | Affected | 0.0656 | 0.5158 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.545C>G | S182C 2D AIThe SynGAP1 missense variant S182C 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 majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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, while the SGM‑Consensus (majority vote) remains pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors 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 | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -12.707 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 0.216 | Likely Benign | -3.14 | Deleterious | 0.983 | Probably Damaging | 0.635 | Possibly Damaging | 3.63 | Benign | 0.00 | Affected | 0.1179 | 0.5800 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.545C>T | S182F 2D AIThe SynGAP1 missense variant S182F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: 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 the Foldetta stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the corroborating high‑accuracy tools, the variant is most likely pathogenic, with no conflict with ClinVar status (which is absent). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -12.027 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.227 | Likely Benign | -4.30 | Deleterious | 0.838 | Possibly Damaging | 0.466 | Possibly Damaging | 3.64 | Benign | 0.00 | Affected | 0.0597 | 0.5482 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.547C>T | H183Y 2D  AIThe SynGAP1 H183Y missense variant 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, 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 show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of computational evidence points to a pathogenic impact, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -9.481 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 0.250 | Likely Benign | -4.48 | Deleterious | 0.818 | Possibly Damaging | 0.255 | Benign | 3.77 | Benign | 0.00 | Affected | 0.0831 | 0.4406 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||||||
| c.550G>A | E184K 2D  AIThe SynGAP1 missense variant E184K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 E184K 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 | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -14.037 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.289 | Likely Benign | -3.31 | Deleterious | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0.2890 | 0.8227 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||||||||||||
| c.550G>C | E184Q 2D  AIThe SynGAP1 missense variant E184Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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, so it does not influence the overall assessment. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -11.927 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.210 | Likely Benign | -2.55 | Deleterious | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 0.1688 | 0.7914 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.551A>C | E184A 2D  AIThe SynGAP1 missense variant E184A has no ClinVar entry and is not reported in gnomAD. 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of computational evidence supports a pathogenic effect for E184A. This prediction 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 | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -11.486 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.338 | Likely Benign | -4.98 | Deleterious | 0.868 | Possibly Damaging | 0.344 | Benign | 3.48 | Benign | 0.00 | Affected | 0.4419 | 0.7381 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.551A>G | E184G 2D  AIThe SynGAP1 missense variant E184G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, 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 preponderance of evidence from both general and high‑accuracy predictors indicates that E184G 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 | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -10.725 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.353 | Likely Benign | -5.52 | Deleterious | 0.970 | Probably Damaging | 0.607 | Possibly Damaging | 3.45 | Benign | 0.00 | Affected | 0.3281 | 0.6534 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.551A>T | E184V 2D  AIThe SynGAP1 missense variant E184V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign calls are made only by REVEL and FATHMM. High‑accuracy assessments reinforce the pathogenic prediction: 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. No Foldetta stability analysis is available for this variant. Overall, the preponderance of evidence indicates that E184V 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 | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -13.119 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.371 | Likely Benign | -5.72 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 3.44 | Benign | 0.00 | Affected | 0.0995 | 0.8511 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.552G>C | E184D 2D  AIThe SynGAP1 E184D 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. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while 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 evidence (six pathogenic vs. three benign predictions) 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. | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -6.753 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | -2.55 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 0.2249 | 0.5394 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.552G>T | E184D 2D AIThe SynGAP1 E184D 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. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while 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 evidence (six pathogenic vs. three benign predictions) 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. | 0.557691 | Disordered | 0.431514 | Uncertain | 0.348 | 0.622 | 0.625 | -6.753 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.195 | Likely Benign | -2.55 | Deleterious | 0.930 | Possibly Damaging | 0.584 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 0.2249 | 0.5394 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.553T>A | S185T 2D AIThe SynGAP1 missense variant S185T 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. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, 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 show AlphaMissense‑Optimized as Uncertain, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -10.943 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.186 | Likely Benign | -2.54 | Deleterious | 0.596 | Possibly Damaging | 0.142 | Benign | 3.60 | Benign | 0.00 | Affected | 0.1484 | 0.6236 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.553T>C | S185P 2D AIThe SynGAP1 missense variant S185P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: 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 evidence from both general and high‑accuracy predictors indicates that the S185P variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -15.129 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.285 | Likely Benign | -4.02 | Deleterious | 0.940 | Possibly Damaging | 0.462 | Possibly Damaging | 3.56 | Benign | 0.00 | Affected | 0.2156 | 0.5242 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.553T>G | S185A 2D AIThe SynGAP1 missense variant S185A 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 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. AlphaMissense‑Optimized is uncertain, and no Foldetta stability result is available. High‑accuracy assessments therefore show a likely pathogenic consensus from SGM‑Consensus, with no contradictory evidence from ClinVar or population databases. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -11.839 | Likely Pathogenic | 0.868 | Likely Pathogenic | Ambiguous | 0.203 | Likely Benign | -2.57 | Deleterious | 0.231 | Benign | 0.107 | Benign | 3.65 | Benign | 0.00 | Affected | 0.5147 | 0.4472 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.554C>A | S185Y 2D AIThe SynGAP1 missense variant S185Y 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 effect comprise 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 impact: AlphaMissense‑Optimized predicts Pathogenic, 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 computational evidence points to a pathogenic 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 Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -13.633 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.316 | Likely Benign | -4.93 | Deleterious | 0.718 | Possibly Damaging | 0.178 | Benign | 3.56 | Benign | 0.00 | Affected | 0.0736 | 0.5439 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||||||||||||
| c.554C>G | S185C 2D AIThe SynGAP1 missense variant S185C has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, while the majority of other in silico predictors (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) all indicate a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (derived from the same set of predictors) also reports 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; this conclusion is not contradicted by any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -10.612 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.266 | Likely Benign | -3.96 | Deleterious | 0.983 | Probably Damaging | 0.635 | Possibly Damaging | 3.54 | Benign | 0.00 | Affected | 0.0989 | 0.6000 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.554C>T | S185F 2D AIThe SynGAP1 missense variant S185F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). 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—predict a pathogenic outcome. The SGM‑Consensus, a majority vote from 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 unavailable. Overall, the preponderance of evidence points to a pathogenic effect for S185F. This conclusion is consistent with the absence of a ClinVar classification, so there is no contradiction with existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -13.327 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.356 | Likely Benign | -5.03 | Deleterious | 0.838 | Possibly Damaging | 0.466 | Possibly Damaging | 3.55 | Benign | 0.00 | Affected | 0.0628 | 0.5563 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.556T>A | L186M 2D  AIThe SynGAP1 missense variant L186M is not 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 are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool rates the variant as uncertain, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (5 pathogenic vs. 3 benign) suggest a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -11.783 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 0.146 | Likely Benign | -1.58 | Neutral | 0.952 | Possibly Damaging | 0.694 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0.0671 | 0.3396 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.556T>G | L186V 2D  AIThe SynGAP1 missense variant L186V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments are mixed: AlphaMissense‑Optimized predicts pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields no clear majority and is therefore unavailable; Foldetta results are also unavailable. Overall, the majority of available predictions (five pathogenic vs. four benign) indicate a pathogenic effect. There is no ClinVar entry to contradict this assessment, so 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. | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -9.385 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.090 | Likely Benign | -2.27 | Neutral | 0.734 | Possibly Damaging | 0.185 | Benign | 3.60 | Benign | 0.00 | Affected | 0.1419 | 0.3665 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.557T>C | L186S 2D  AIThe SynGAP1 missense variant L186S 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 (majority vote). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant 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 from both general and high‑accuracy predictors 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 | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -13.906 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.250 | Likely Benign | -4.73 | Deleterious | 0.952 | Possibly Damaging | 0.601 | Possibly Damaging | 3.51 | Benign | 0.00 | Affected | 0.3214 | 0.0808 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.557T>G | L186W 2D  AIThe SynGAP1 missense variant L186W has no ClinVar entry and is not reported in gnomAD. 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 outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus reports it as Likely Pathogenic. No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -16.177 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.274 | Likely Benign | -4.78 | Deleterious | 0.996 | Probably Damaging | 0.819 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 0.0539 | 0.3138 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.558G>C | L186F 2D  AIThe SynGAP1 missense variant L186F is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM. In contrast, tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote) 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 computational evidence points to a pathogenic effect, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | Uncertain | 1 | -11.861 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | -3.03 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.50 | Benign | 0.00 | Affected | 0.0524 | 0.3177 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||
| c.558G>T | L186F 2D AIThe SynGAP1 missense variant L186F 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “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 computational 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 | 0.458154 | Structured | 0.428613 | Uncertain | 0.397 | 0.617 | 0.500 | -11.861 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.132 | Likely Benign | -3.03 | Deleterious | 0.009 | Benign | 0.012 | Benign | 3.50 | Benign | 0.00 | Affected | 0.0524 | 0.3177 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.55G>A | A19T 2D  AIThe SynGAP1 missense variant A19T 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. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.443393 | Uncertain | 0.378 | 0.906 | 0.500 | -3.422 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -0.02 | Neutral | 0.371 | Benign | 0.036 | Benign | 4.14 | Benign | 0.00 | Affected | 0.2357 | 0.7248 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.55G>C | A19P 2D  AIThe SynGAP1 missense variant A19P is reported in gnomAD (variant ID 6‑33420319‑G‑C) but has no ClinVar entry. 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 only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: 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 impact, and this 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 | 0.529623 | Disordered | 0.443393 | Uncertain | 0.378 | 0.906 | 0.500 | 6-33420319-G-C | -3.579 | Likely Benign | 0.184 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.09 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2609 | 0.6018 | -1 | 1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||||
| c.55G>T | A19S 2D  AIThe SynGAP1 missense variant A19S 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 confirm this: 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 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 | 0.529623 | Disordered | 0.443393 | Uncertain | 0.378 | 0.906 | 0.500 | -2.905 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.21 | Neutral | 0.225 | Benign | 0.027 | Benign | 4.17 | Benign | 0.00 | Affected | 0.3273 | 0.6260 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.560T>A | L187Q 2D  AIThe SynGAP1 missense variant L187Q 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, and PROVEAN) all indicate likely pathogenicity. High‑accuracy assessments further support a deleterious effect: 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, was not available for this variant. Overall, the preponderance of evidence from multiple in silico predictors points to a pathogenic effect for the SynGAP1 L187Q 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 | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -13.063 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.322 | Likely Benign | -4.31 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 3.72 | Benign | 0.00 | Affected | 0.1251 | 0.1060 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.560T>G | L187R 2D  AIThe SynGAP1 missense variant L187R 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 (majority vote). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a deleterious effect, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant 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 from both general and high‑accuracy predictors 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 | 0.465241 | Structured | 0.428046 | Uncertain | 0.367 | 0.625 | 0.375 | -14.118 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.332 | Likely Benign | -4.38 | Deleterious | 0.917 | Possibly Damaging | 0.467 | Possibly Damaging | 3.72 | Benign | 0.00 | Affected | 0.1481 | 0.0702 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.562A>C | S188R 2D  AIThe SynGAP1 missense variant S188R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S188R variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.269 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.562A>G | S188G 2D  AIThe SynGAP1 missense variant S188G 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 effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus (SGM‑Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is “Likely Pathogenic.” AlphaMissense‑Optimized returns an uncertain result, and Foldetta (which would combine FoldX‑MD and Rosetta outputs) has no available data for this variant. Based on the overall distribution of predictions, the variant is most likely pathogenic; this assessment 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 | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -10.113 | Likely Pathogenic | 0.919 | Likely Pathogenic | Ambiguous | 0.123 | Likely Benign | -3.10 | Deleterious | 0.882 | Possibly Damaging | 0.404 | Benign | 3.91 | Benign | 0.00 | Affected | 0.3045 | 0.5542 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.562A>T | S188C 2D AIThe SynGAP1 missense variant S188C is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default, all of which classify the substitution as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized yields an uncertain result, while Foldetta data are unavailable. Based on the preponderance of pathogenic predictions and the SGM‑Consensus, the variant is most likely pathogenic; 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 | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -8.670 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.111 | Likely Benign | -2.96 | Deleterious | 0.999 | Probably Damaging | 0.956 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 0.1007 | 0.6737 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.563G>T | S188I 2D  AIThe SynGAP1 missense variant S188I 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, while the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic or likely pathogenic outcome. 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 also pathogenic; Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for S188I, 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 | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -12.133 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.205 | Likely Benign | -3.98 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.0878 | 0.6335 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.564T>A | S188R 2D AIThe SynGAP1 missense variant S188R 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 FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: 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, a protein‑folding stability method, did not provide a result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S188R variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.264 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.564T>G | S188R 2D AIThe SynGAP1 missense variant S188R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: 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, a protein‑folding stability method, did not provide a result 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 is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -11.567 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.263 | Likely Benign | -3.82 | Deleterious | 0.985 | Probably Damaging | 0.767 | Possibly Damaging | 3.92 | Benign | 0.00 | Affected | 0.0916 | 0.4236 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.566C>A | P189H 2D  AIThe SynGAP1 missense variant P189H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—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 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 P189H 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 | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -9.633 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.298 | Likely Benign | -6.49 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 4.00 | Benign | 0.00 | Affected | 0.1620 | 0.5327 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.56C>A | A19D 2D  AIThe SynGAP1 missense variant A19D is listed in gnomAD (ID 6‑33420320‑C‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, 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 stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, 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 | 0.529623 | Disordered | 0.443393 | Uncertain | 0.378 | 0.906 | 0.500 | 6-33420320-C-A | 2 | 1.30e-6 | -3.746 | Likely Benign | 0.573 | Likely Pathogenic | Likely Benign | 0.055 | Likely Benign | -0.08 | Neutral | 0.588 | Possibly Damaging | 0.054 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2508 | 0.2734 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||
| c.56C>G | A19G 2D  AIThe SynGAP1 missense variant A19G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The prediction 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 Benign | 0.529623 | Disordered | 0.443393 | Uncertain | 0.378 | 0.906 | 0.500 | -3.525 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -0.45 | Neutral | 0.371 | Benign | 0.036 | Benign | 4.10 | Benign | 0.00 | Affected | 0.2324 | 0.5447 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.56C>T | A19V 2D  AIThe SynGAP1 missense variant A19V is reported in gnomAD (ID 6‑33420320‑C‑T) but has no ClinVar entry. 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 only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are unavailable. Overall, the consensus of available predictions points to a benign impact for A19V, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.443393 | Uncertain | 0.378 | 0.906 | 0.500 | 6-33420320-C-T | -3.157 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.063 | Likely Benign | 0.42 | Neutral | 0.371 | Benign | 0.036 | Benign | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1804 | 0.6942 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.571A>T | S191C 2D AIThe SynGAP1 missense variant S191C is not 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. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—leans pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of tools and the SGM Consensus predict a pathogenic impact, so 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. | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.009 | In-Between | 0.709 | Likely Pathogenic | Likely Benign | 0.288 | Likely Benign | -3.39 | Deleterious | 0.983 | Probably Damaging | 0.635 | Possibly Damaging | 3.73 | Benign | 0.00 | Affected | 0.1064 | 0.7134 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||||
| c.572G>T | S191I 2D AIThe SynGAP1 missense variant S191I is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split opinion: benign predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), and FATHMM, while pathogenic predictions arise from PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. When the predictions are grouped by consensus, four tools favor benign and four favor pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, whereas 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 variant. Taken together, the majority of evidence, including the SGM Consensus, 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 | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -11.271 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 0.283 | Likely Benign | -4.51 | Deleterious | 0.421 | Benign | 0.086 | Benign | 3.76 | Benign | 0.00 | Affected | 0.0954 | 0.6842 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.581A>T | E194V 2D AIThe SynGAP1 missense variant E194V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of computational 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 | 0.418646 | Structured | 0.430723 | Uncertain | 0.346 | 0.551 | 0.125 | -10.261 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.284 | Likely Benign | -4.67 | Deleterious | 0.580 | Possibly Damaging | 0.254 | Benign | 3.94 | Benign | 0.00 | Affected | 0.0623 | 0.5469 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.587T>C | L196S 2D AIThe SynGAP1 missense variant L196S 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 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect comprise PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is Likely Pathogenic, while Foldetta results are unavailable. 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 | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -9.987 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.353 | Likely Benign | -4.75 | Deleterious | 0.437 | Benign | 0.186 | Benign | 3.65 | Benign | 0.00 | Affected | 0.3473 | 0.0736 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||||||||||||
| c.587T>G | L196W 2D AIThe SynGAP1 missense variant L196W has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and FATHMM, whereas the remaining 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)—all predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for this variant, 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 | 0.284882 | Structured | 0.429452 | Uncertain | 0.489 | 0.521 | 0.125 | -12.148 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.293 | Likely Benign | -4.91 | Deleterious | 0.992 | Probably Damaging | 0.869 | Possibly Damaging | 3.58 | Benign | 0.00 | Affected | 0.0551 | 0.2718 | -2 | -2 | -4.7 | 73.05 | |||||||||||||||||||||||||||||||||||||||
| c.58C>A | P20T 2D  AIThe SynGAP1 missense variant P20T is reported in gnomAD (ID 6‑33420322‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict pathogenic. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence, including the high‑accuracy tools, points to the variant being most likely benign, 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 Benign | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | 6-33420322-C-A | -3.258 | Likely Benign | 0.223 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.50 | Neutral | 0.909 | Possibly Damaging | 0.641 | Possibly Damaging | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1781 | 0.6640 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.58C>G | P20A 2D  AIThe SynGAP1 missense variant P20A 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‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for P20A, 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 | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | -3.120 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.31 | Neutral | 0.805 | Possibly Damaging | 0.539 | Possibly Damaging | 4.31 | Benign | 0.00 | Affected | 0.3753 | 0.5520 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.58C>T | P20S 2D  AIThe SynGAP1 missense variant P20S is reported in gnomAD (ID 6‑33420322‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from the four benign‑oriented tools). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 effect for P20S, 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 | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | 6-33420322-C-T | -3.054 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.25 | Neutral | 0.909 | Possibly Damaging | 0.641 | Possibly Damaging | 4.30 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3732 | 0.5920 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.590A>T | E197V 2D AIThe SynGAP1 missense variant E197V is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split opinion: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. When predictions are grouped by consensus, four tools predict benign and four predict pathogenic. 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. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the preponderance of evidence from both general and high‑accuracy predictors indicates that E197V is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | -9.023 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.247 | Likely Benign | -4.51 | Deleterious | 0.396 | Benign | 0.099 | Benign | 4.01 | Benign | 0.00 | Affected | 0.0490 | 0.6024 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||||||||||||
| c.592C>A | L198I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198I 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, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain or inconclusive results come from AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the majority 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. | 0.444081 | Structured | 0.431715 | Uncertain | 0.572 | 0.485 | 0.125 | -10.411 | Likely Pathogenic | 0.563 | Ambiguous | Likely Benign | 0.59 | Ambiguous | 0.1 | 0.70 | Ambiguous | 0.65 | Ambiguous | 0.10 | Likely Benign | 0.234 | Likely Benign | -1.72 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 3.43 | Benign | 0.00 | Affected | 0.0921 | 0.3307 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||
| c.592C>G | L198V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L198V variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (3 pathogenic vs. 1 benign) indicates pathogenicity; Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this is not contradicted by any ClinVar annotation (none exists). Thus, the variant is most likely pathogenic based on current computational predictions. 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 | -9.343 | Likely Pathogenic | 0.747 | Likely Pathogenic | Likely Benign | 1.10 | Ambiguous | 0.2 | 1.24 | Ambiguous | 1.17 | Ambiguous | 0.34 | Likely Benign | 0.265 | Likely Benign | -2.54 | Deleterious | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 3.44 | Benign | 0.00 | Affected | 0.1520 | 0.3017 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.592C>T | L198F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L198F has no ClinVar entry and is absent from gnomAD. Functional prediction tools split into two consensus groups: benign predictions come from REVEL, Rosetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments are mixed: AlphaMissense‑Optimized and Foldetta report uncertain results, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect. No evidence from ClinVar contradicts these findings. Overall, the preponderance of pathogenic predictions and the SGM‑Consensus designation suggest that the variant is most likely pathogenic. 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 | -10.602 | Likely Pathogenic | 0.930 | Likely Pathogenic | Ambiguous | 1.03 | Ambiguous | 0.2 | 0.27 | Likely Benign | 0.65 | Ambiguous | 0.00 | Likely Benign | 0.282 | Likely Benign | -3.33 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 3.39 | Benign | 0.00 | Affected | 0.0586 | 0.3112 | 2 | 0 | -1.0 | 34.02 | ||||||||||||||||||||||||||||||
| 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.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.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.59C>A | P20H 2D AIThe SynGAP1 missense variant P20H is reported in gnomAD (ID 6‑33420323‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates benign. Foldetta results are unavailable. Overall, the preponderance of evidence from both consensus and high‑accuracy tools points to a benign effect for P20H, and this conclusion does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | 6-33420323-C-A | -4.450 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.132 | Likely Benign | -0.69 | Neutral | 0.992 | Probably Damaging | 0.893 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1834 | 0.5066 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||
| c.59C>G | P20R 2D  AIThe SynGAP1 missense variant P20R is listed in ClinVar (ID 566521.0) 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‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. 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 current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | Uncertain | 1 | -3.548 | Likely Benign | 0.434 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -0.15 | Neutral | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1509 | 0.3272 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||
| c.59C>T | P20L 2D  AIThe SynGAP1 missense variant P20L (ClinVar ID 1185912.0) is listed as “Uncertain” in ClinVar and is not reported in 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, and SIFT; AlphaMissense‑Default remains uncertain. 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, and 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 | 0.529623 | Disordered | 0.442804 | Uncertain | 0.448 | 0.899 | 0.500 | Uncertain | 3 | -3.289 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.100 | Likely Benign | -0.44 | Neutral | 0.909 | Possibly Damaging | 0.713 | Possibly Damaging | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2479 | 0.7258 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||
| c.5G>A | S2N 2D  AIThe SynGAP1 missense variant S2N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33420269‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 preponderance of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | Uncertain | 2 | 6-33420269-G-A | 3 | 1.96e-6 | -4.104 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.36 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.06 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1484 | 0.5637 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||
| c.5G>C | S2T 2D AIThe SynGAP1 missense variant S2T is reported in gnomAD (variant ID 6‑33420269‑G‑C) but has no ClinVar entry. 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. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. 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 points to a benign impact for S2T, 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 | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | 6-33420269-G-C | -4.443 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.55 | Neutral | 0.052 | Benign | 0.004 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1575 | 0.6954 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.5G>T | S2I 2D AIThe SynGAP1 missense variant S2I is catalogued in gnomAD (6‑33420269‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus, derived from the majority of the high‑confidence predictors, is benign. 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 indicates that S2I is most likely benign, and this assessment does not contradict any ClinVar status, as none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | 6-33420269-G-T | -4.947 | Likely Benign | 0.439 | Ambiguous | Likely Benign | 0.031 | Likely Benign | -0.59 | Neutral | 0.212 | Benign | 0.020 | Benign | 4.04 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1021 | 0.5980 | -2 | -1 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||
| c.617T>A | I206N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206N 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 and FATHMM, while 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 a deleterious outcome: 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 stability predictions, is pathogenic. No prediction or folding 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 the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -15.211 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.98 | Destabilizing | 0.2 | 2.57 | Destabilizing | 2.78 | Destabilizing | 2.04 | Destabilizing | 0.334 | Likely Benign | -5.55 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 3.62 | Benign | 0.00 | Affected | 0.0689 | 0.0340 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.617T>C | I206T 2D  AIThe SynGAP1 I206T 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, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give consistent results: 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 overall evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not currently listed. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -10.812 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 2.43 | Destabilizing | 0.5 | 2.68 | Destabilizing | 2.56 | Destabilizing | 1.94 | Destabilizing | 0.252 | Likely Benign | -3.78 | Deleterious | 0.421 | Benign | 0.156 | Benign | 3.65 | Benign | 0.00 | Affected | 0.0830 | 0.0669 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.617T>G | I206S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I206S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and polyPhen‑2 HumVar. All other evaluated algorithms (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is pathogenic. Based on the preponderance of evidence from these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -13.711 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.73 | Destabilizing | 0.3 | 3.89 | Destabilizing | 3.81 | Destabilizing | 1.74 | Destabilizing | 0.251 | Likely Benign | -4.86 | Deleterious | 0.838 | Possibly Damaging | 0.368 | Benign | 3.63 | Benign | 0.00 | Affected | 0.2189 | 0.0728 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.61T>A | F21I 2D  AIThe SynGAP1 missense variant F21I is listed in gnomAD (ID 6‑33420325‑T‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, 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 show AlphaMissense‑Optimized as benign and the SGM‑Consensus also benign; Foldetta results are unavailable. Taken together, the majority of evidence points to a benign effect. Thus, the variant is most likely benign, 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 Benign | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | 6-33420325-T-A | -3.678 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.141 | Likely Benign | 0.56 | Neutral | 0.462 | Possibly Damaging | 0.307 | Benign | 4.29 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2703 | 0.2469 | 0 | 1 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.61T>C | F21L 2D  AIThe SynGAP1 missense variant F21L is reported in gnomAD (ID 6‑33420325‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized uncertain, SGM‑Consensus Likely Benign, and no Foldetta stability data is available. Overall, the balance of evidence favors a benign classification, 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 | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | 6-33420325-T-C | -2.480 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.140 | Likely Benign | 0.15 | Neutral | 0.140 | Benign | 0.153 | Benign | 4.34 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2680 | 0.3250 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.61T>G | F21V 2D  AIThe SynGAP1 missense variant F21V is listed in gnomAD (ID 6‑33420325‑T‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, 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 points to a benign impact, and this conclusion 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 | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | 6-33420325-T-G | -2.823 | Likely Benign | 0.563 | Ambiguous | Likely Benign | 0.224 | Likely Benign | 0.64 | Neutral | 0.462 | Possibly Damaging | 0.307 | Benign | 4.44 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2536 | 0.2497 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||
| 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.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.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.628C>A | H210N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 H210N 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, and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus score (Likely Pathogenic). Two tools give uncertain results: Foldetta (combining FoldX‑MD and Rosetta outputs) and Rosetta alone. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points toward a pathogenic effect for H210N. 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 | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -13.699 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.19 | Likely Benign | 0.3 | 1.24 | Ambiguous | 0.72 | Ambiguous | 1.12 | Destabilizing | 0.375 | Likely Benign | -6.01 | Deleterious | 0.895 | Possibly Damaging | 0.533 | Possibly Damaging | 3.11 | Benign | 0.00 | Affected | 0.1166 | 0.1839 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| 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.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.629A>C | H210P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210P 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; all other evaluated algorithms—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 from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -14.634 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 2.26 | Destabilizing | 0.5 | 2.80 | Destabilizing | 2.53 | Destabilizing | 1.00 | Destabilizing | 0.512 | Likely Pathogenic | -8.55 | Deleterious | 0.989 | Probably Damaging | 0.795 | Possibly Damaging | 3.09 | Benign | 0.00 | Affected | 0.1805 | 0.3175 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| 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.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.62T>A | F21Y 2D  AIThe SynGAP1 missense variant F21Y is listed in gnomAD (ID 6‑33420326‑T‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates a likely benign classification. No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for F21Y, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | 6-33420326-T-A | -3.712 | Likely Benign | 0.352 | Ambiguous | Likely Benign | 0.088 | Likely Benign | -0.23 | Neutral | 0.273 | Benign | 0.153 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1698 | 0.2608 | 3 | 7 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.62T>C | F21S 2D  AIThe SynGAP1 missense variant F21S 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, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. 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 Benign | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | -2.396 | Likely Benign | 0.745 | Likely Pathogenic | Likely Benign | 0.182 | Likely Benign | -0.22 | Neutral | 0.462 | Possibly Damaging | 0.307 | Benign | 4.15 | Benign | 0.00 | Affected | 0.4793 | 0.1133 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||||||||||||
| c.62T>G | F21C 2D  AIThe SynGAP1 missense variant F21C 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 the SGM‑Consensus (Likely Benign). 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, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for F21C. 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 Benign | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | -3.698 | Likely Benign | 0.686 | Likely Pathogenic | Likely Benign | 0.151 | Likely Benign | -0.31 | Neutral | 0.880 | Possibly Damaging | 0.759 | Possibly Damaging | 4.12 | Benign | 0.00 | Affected | 0.2873 | 0.2171 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||||||||||||
| c.630C>A | H210Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls are made by premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN, favors a pathogenic outcome (3/4). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) also predicts pathogenic. Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta, is inconclusive and therefore not used as evidence. Overall, the majority of reliable predictors indicate a pathogenic effect for H210Q, and this conclusion does not conflict with any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.144935 | Structured | 0.390904 | Uncertain | 0.872 | 0.298 | 0.125 | -12.639 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.3 | 1.96 | Ambiguous | 1.11 | Ambiguous | 1.20 | Destabilizing | 0.258 | Likely Benign | -6.84 | Deleterious | 0.141 | Benign | 0.064 | Benign | 3.10 | Benign | 0.00 | Affected | 0.1016 | 0.2852 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.630C>G | H210Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H210Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar) and FATHMM, whereas pathogenic calls come from premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default and AlphaMissense‑Optimized. When predictions are grouped, five tools favor a benign effect and six favor a pathogenic effect. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic, and the Foldetta stability analysis is inconclusive. No evidence from ClinVar contradicts these findings. Therefore, the variant is most likely pathogenic based on the aggregate computational evidence. 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 | -12.639 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.26 | Likely Benign | 0.3 | 1.96 | Ambiguous | 1.11 | Ambiguous | 1.20 | Destabilizing | 0.258 | Likely Benign | -6.84 | Deleterious | 0.141 | Benign | 0.064 | Benign | 3.10 | Benign | 0.00 | Affected | 0.1016 | 0.2852 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.635C>A | S212Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212Y is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include FoldX, FATHMM, and premPS. In contrast, a majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, is inconclusive for this variant. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence from multiple in silico predictors indicates that S212Y is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -14.812 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.43 | Likely Benign | 0.5 | 2.32 | Destabilizing | 1.38 | Ambiguous | 0.22 | Likely Benign | 0.819 | Likely Pathogenic | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.0555 | 0.6120 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.635C>G | S212C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include FoldX, premPS, and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors 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 | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -11.656 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.16 | Likely Benign | 0.1 | 0.98 | Ambiguous | 0.57 | Ambiguous | 0.47 | Likely Benign | 0.840 | Likely Pathogenic | -4.29 | Deleterious | 0.999 | Probably Damaging | 0.990 | Probably Damaging | 5.73 | Benign | 0.00 | Affected | 0.0785 | 0.6270 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.635C>T | S212F 2D AIThe SynGAP1 missense variant S212F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and premPS, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) predict a pathogenic outcome. The remaining tools, Foldetta and Rosetta, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Based on the overall consensus of the majority of predictors and the high‑accuracy tools, 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 | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -14.029 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.11 | Likely Benign | 1.6 | 0.88 | Ambiguous | 0.50 | Ambiguous | -0.02 | Likely Benign | 0.820 | Likely Pathogenic | -5.15 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.0503 | 0.6259 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.638T>A | I213N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I213N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; FoldX is uncertain and is treated as unavailable. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -15.069 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 0.8 | 2.81 | Destabilizing | 2.26 | Destabilizing | 1.85 | Destabilizing | 0.862 | Likely Pathogenic | -5.81 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | 0.0750 | 0.0412 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.638T>C | I213T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213T missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining evidence—SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently indicates pathogenicity. FoldX, Rosetta, and Foldetta provide uncertain results. 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 remains uncertain. Overall, the preponderance of evidence supports a pathogenic classification for I213T, 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 | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -11.080 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.46 | Ambiguous | 0.8 | 1.32 | Ambiguous | 1.39 | Ambiguous | 1.49 | Destabilizing | 0.882 | Likely Pathogenic | -3.99 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.82 | Benign | 0.00 | Affected | 0.0905 | 0.0708 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.638T>G | I213S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213S missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -12.858 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.00 | Destabilizing | 1.1 | 2.95 | Destabilizing | 2.48 | Destabilizing | 1.53 | Destabilizing | 0.879 | Likely Pathogenic | -4.88 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 5.83 | Benign | 0.00 | Affected | 0.2290 | 0.0800 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.63C>A | F21L 2D AIThe SynGAP1 missense variant F21L is reported in gnomAD (ID 6‑33420327‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, 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 majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. 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. | Likely Benign | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | 6-33420327-C-A | -2.480 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | 0.15 | Neutral | 0.140 | Benign | 0.153 | Benign | 4.34 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2680 | 0.3250 | 0 | 2 | 1.0 | -34.02 | ||||||||||||||||||||||||||||||||||||
| c.63C>G | F21L 2D AIThe SynGAP1 missense variant F21L is not 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, ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, while AlphaMissense‑Optimized remains uncertain and Foldetta is unavailable. Overall, the majority of evidence points to a benign impact. The predictions do not contradict the ClinVar status, which is currently unreported. Thus, based on the available computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.443284 | Uncertain | 0.369 | 0.897 | 0.500 | -2.480 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.104 | Likely Benign | 0.15 | Neutral | 0.140 | Benign | 0.153 | Benign | 4.34 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2680 | 0.3250 | 0 | 2 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||
| c.641T>A | L214Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change at residue 214 (Leu→Gln) is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, the majority (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic effect, while only FATHMM predicts a benign outcome. Three tools (FoldX, Rosetta, Foldetta) return uncertain results. 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 is uncertain. Taken together, the overwhelming consensus of pathogenic predictions indicates that the variant is most likely pathogenic, with no ClinVar evidence contradicting this assessment. 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 | -10.119 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.60 | Ambiguous | 0.6 | 1.71 | Ambiguous | 1.66 | Ambiguous | 1.73 | Destabilizing | 0.912 | Likely Pathogenic | -5.12 | Deleterious | 0.997 | Probably Damaging | 0.936 | Probably Damaging | 5.74 | Benign | 0.00 | Affected | 0.1140 | 0.0930 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.641T>C | L214P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L214P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, while the remaining 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and the consensus of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) uniformly 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, 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 overwhelming agreement among predictive algorithms, 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 | PH | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -11.348 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.38 | Destabilizing | 1.3 | 7.51 | Destabilizing | 5.45 | Destabilizing | 1.30 | Destabilizing | 0.930 | Likely Pathogenic | -5.98 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.3448 | 0.1553 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.641T>G | L214R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L214R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the evidence strongly favors a pathogenic effect for this variant, 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 | 0.155435 | Structured | 0.372604 | Uncertain | 0.818 | 0.302 | 0.125 | -11.458 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.35 | Ambiguous | 0.6 | 0.92 | Ambiguous | 1.14 | Ambiguous | 1.68 | Destabilizing | 0.927 | Likely Pathogenic | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | 0.1335 | 0.0772 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.643G>T | G215C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215C 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 premPS and FATHMM; those that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Rosetta gives an uncertain result and is listed separately. High‑accuracy methods all predict pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Based on the overwhelming agreement among both general and high‑accuracy predictors, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -12.295 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.39 | Destabilizing | 0.2 | 1.76 | Ambiguous | 2.08 | Destabilizing | 0.33 | Likely Benign | 0.869 | Likely Pathogenic | -7.69 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 5.56 | Benign | 0.00 | Affected | 0.1274 | 0.4640 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.644G>T | G215V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215V is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining twelve tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as pathogenic. premPS is uncertain and does not influence the consensus. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or 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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -12.960 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.69 | Destabilizing | 0.2 | 5.41 | Destabilizing | 4.55 | Destabilizing | 0.53 | Ambiguous | 0.884 | Likely Pathogenic | -7.66 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.56 | Benign | 0.00 | Affected | 0.1087 | 0.4777 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.64A>G | R22G 2D AIThe SynGAP1 missense variant R22G is reported in ClinVar as “Not submitted” and is present in gnomAD (ID 6‑33420328‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. 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 predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of computational evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | 6-33420328-A-G | -3.628 | Likely Benign | 0.322 | Likely Benign | Likely Benign | 0.185 | Likely Benign | -0.42 | Neutral | 0.462 | Possibly Damaging | 0.152 | Benign | 4.19 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3590 | 0.4098 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||
| c.655T>C | C219R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219R is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, while the remaining 13 tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -15.727 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.00 | Destabilizing | 1.5 | 2.20 | Destabilizing | 2.60 | Destabilizing | 1.33 | Destabilizing | 0.904 | Likely Pathogenic | -9.90 | Deleterious | 0.969 | Probably Damaging | 0.680 | Possibly Damaging | 5.80 | Benign | 0.00 | Affected | 0.1381 | 0.1837 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| c.656G>A | C219Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict a pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Based on the preponderance of evidence, the variant is most likely pathogenic, a conclusion that does not contradict its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | Uncertain | 1 | -14.797 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 8.98 | Destabilizing | 2.0 | 2.84 | Destabilizing | 5.91 | Destabilizing | 0.55 | Ambiguous | 0.812 | Likely Pathogenic | -9.09 | Deleterious | 0.990 | Probably Damaging | 0.758 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0.0772 | 0.3285 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||
| c.656G>T | C219F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219F 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 premPS and FATHMM, while the remaining 13 tools—including SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized reports pathogenic; 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 pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -14.322 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.31 | Destabilizing | 1.9 | 2.45 | Destabilizing | 4.88 | Destabilizing | 0.47 | Likely Benign | 0.814 | Likely Pathogenic | -9.18 | Deleterious | 0.940 | Possibly Damaging | 0.505 | Possibly Damaging | 5.82 | Benign | 0.00 | Affected | 0.0959 | 0.3804 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.657T>G | C219W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C219W is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and premPS are inconclusive. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.426845 | Uncertain | 0.903 | 0.279 | 0.000 | -16.565 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 10.10 | Destabilizing | 3.6 | 1.20 | Ambiguous | 5.65 | Destabilizing | 0.52 | Ambiguous | 0.706 | Likely Pathogenic | -9.23 | Deleterious | 0.997 | Probably Damaging | 0.808 | Possibly Damaging | 5.77 | Benign | 0.00 | Affected | 0.1131 | 0.3285 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.659T>A | F220Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and polyPhen‑2 HumVar. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is classified as pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain and therefore not considered evidence. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that F220Y is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.541 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.25 | Destabilizing | 0.1 | 0.35 | Likely Benign | 1.30 | Ambiguous | 1.14 | Destabilizing | 0.879 | Likely Pathogenic | -2.54 | Deleterious | 0.928 | Possibly Damaging | 0.395 | Benign | 4.07 | Benign | 0.00 | Affected | 0.1479 | 0.2661 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.659T>G | F220C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F220C is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. 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 (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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.219301 | Structured | 0.429422 | Uncertain | 0.898 | 0.295 | 0.000 | -12.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.67 | Destabilizing | 0.0 | 5.03 | Destabilizing | 4.35 | Destabilizing | 2.22 | Destabilizing | 0.941 | Likely Pathogenic | -6.72 | Deleterious | 0.994 | Probably Damaging | 0.753 | Possibly Damaging | 4.03 | Benign | 0.00 | Affected | 0.2264 | 0.2012 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.65G>A | R22K 2D  AIThe SynGAP1 missense variant R22K is reported in gnomAD (variant ID 6‑33420329‑G‑A) but has no ClinVar entry. 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. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. 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 preponderance of evidence points to a benign effect for R22K, 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 | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | 6-33420329-G-A | -4.736 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.032 | Likely Benign | -0.12 | Neutral | 0.140 | Benign | 0.067 | Benign | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 0.6413 | 0.5384 | Strenghten | 2 | 3 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||
| c.65G>C | R22T 2D  AIThe SynGAP1 missense variant R22T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls from REVEL, PROVEAN, polyPhen2_HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen2_HumDiv and SIFT. The majority‑vote SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy predictors further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta predictions are not available. Given the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign. This assessment aligns with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | -4.079 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -0.21 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.23 | Benign | 0.00 | Affected | 0.2140 | 0.5599 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.65G>T | R22I 2D  AIThe SynGAP1 missense variant R22I 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, 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 Benign and the SGM‑Consensus as Likely Benign; 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 | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | -4.849 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | 0.06 | Neutral | 0.676 | Possibly Damaging | 0.308 | Benign | 4.20 | Benign | 0.00 | Affected | 0.2120 | 0.5048 | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.662A>G | E221G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221G 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 polyPhen‑2 HumVar and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) indicate a pathogenic impact; FoldX, Rosetta, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Based on the collective evidence, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | Uncertain | 1 | -12.221 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.40 | Ambiguous | 0.1 | 1.74 | Ambiguous | 1.57 | Ambiguous | 0.71 | Ambiguous | 0.863 | Likely Pathogenic | -5.56 | Deleterious | 0.596 | Possibly Damaging | 0.201 | Benign | 5.79 | Benign | 0.00 | Affected | 0.2611 | 0.6370 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||
| c.662A>T | E221V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221V missense variant is reported in ClinVar as Pathogenic (ClinVar ID 2413181.0) and is not found in gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Benign predictions are limited to premPS, polyPhen‑2 HumVar, and FATHMM. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy assessments reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus also indicates Likely Pathogenic, while Foldetta remains Uncertain. Taken together, the preponderance of evidence supports a pathogenic effect for E221V, and this conclusion aligns with the ClinVar classification, showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | Likely Pathogenic | 1 | -14.954 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | -0.66 | Ambiguous | 0.2 | -0.89 | Ambiguous | -0.78 | Ambiguous | 0.49 | Likely Benign | 0.875 | Likely Pathogenic | -5.54 | Deleterious | 0.596 | Possibly Damaging | 0.203 | Benign | 5.86 | Benign | 0.00 | Affected | 3.41 | 13 | 0.0806 | 0.8138 | -2 | -2 | 7.7 | -29.98 | 234.5 | 50.6 | 0.0 | 0.0 | -0.4 | 0.2 | X | Uncertain | The introduced residue Val221 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the carboxylate group of Glu221, Val221 cannot form hydrogen bonds with Thr223 or a salt bridge with the amino group of the Lys207 side chain. Despite this, the WT simulations containing Glu221 do not show significant differences compared to the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||||||
| c.665T>A | V222E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V222E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this conclusion is consistent with the lack of ClinVar reporting (i.e., no contradictory evidence). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -18.017 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.04 | Destabilizing | 0.2 | 3.46 | Destabilizing | 3.75 | Destabilizing | 1.64 | Destabilizing | 0.960 | Likely Pathogenic | -5.20 | Deleterious | 0.998 | Probably Damaging | 0.987 | Probably Damaging | 5.20 | Benign | 0.00 | Affected | 0.0833 | 0.1495 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.665T>G | V222G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V222G resides in the PH domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining eleven tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently contains no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -14.857 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 4.54 | Destabilizing | 0.4 | 5.25 | Destabilizing | 4.90 | Destabilizing | 2.05 | Destabilizing | 0.962 | Likely Pathogenic | -6.05 | Deleterious | 0.987 | Probably Damaging | 0.998 | Probably Damaging | 5.21 | Benign | 0.00 | Affected | 0.1678 | 0.1996 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.66A>C | R22S 2D  AIThe SynGAP1 missense variant R22S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; a Foldetta stability prediction is 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 | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | -3.419 | Likely Benign | 0.602 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | 0.01 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3252 | 0.5187 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.66A>T | R22S 2D AIThe SynGAP1 missense variant R22S is listed in gnomAD (ID 6‑33420330‑A‑T) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. 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 reported result for this variant, so its stability impact is unavailable. Overall, the majority of evidence points to a benign effect, and this is not in conflict with ClinVar, which has no classification for R22S. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.538167 | Disordered | 0.441505 | Uncertain | 0.377 | 0.891 | 0.500 | 6-33420330-A-T | -3.419 | Likely Benign | 0.602 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | 0.01 | Neutral | 0.462 | Possibly Damaging | 0.227 | Benign | 4.28 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3252 | 0.5187 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||
| c.67G>A | D23N 2D  AIThe SynGAP1 D23N missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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. | Likely Benign | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | -3.918 | Likely Benign | 0.719 | Likely Pathogenic | Likely Benign | 0.077 | Likely Benign | -1.88 | Neutral | 0.805 | Possibly Damaging | 0.539 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 0.2236 | 0.8784 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.67G>C | D23H 2D AIThe SynGAP1 D23H 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 effect are 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 show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). 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 | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | -3.801 | Likely Benign | 0.867 | Likely Pathogenic | Ambiguous | 0.103 | Likely Benign | -2.46 | Neutral | 0.972 | Probably Damaging | 0.861 | Possibly Damaging | 3.47 | Benign | 0.00 | Affected | 0.2644 | 0.9017 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||||||||||||
| c.67G>T | D23Y 2D AIThe SynGAP1 D23Y missense variant is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33420331‑G‑T). Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic impact. 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. | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | 6-33420331-G-T | -4.191 | Likely Benign | 0.729 | Likely Pathogenic | Likely Benign | 0.142 | Likely Benign | -2.87 | Deleterious | 0.972 | Probably Damaging | 0.861 | Possibly Damaging | 3.46 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1013 | 0.7951 | -3 | -4 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||
| c.686A>T | K229I 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K229I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from FoldX, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are returned by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports benign. No prediction is inconclusive. Overall, the majority of tools, including the high‑accuracy ones, lean toward pathogenicity, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -15.276 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.03 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.33 | Likely Benign | -0.19 | Likely Benign | 0.833 | Likely Pathogenic | -6.52 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.92 | Benign | 0.00 | Affected | 0.1202 | 0.3711 | -2 | -3 | 8.4 | -15.01 | |||||||||||||||||||||||||||||
| c.68A>C | D23A 2D  AIThe SynGAP1 D23A 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while 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 predictions (five pathogenic versus four benign) suggest a pathogenic impact. This conclusion does not contradict ClinVar status, as the variant has no existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | -2.732 | Likely Benign | 0.777 | Likely Pathogenic | Likely Benign | 0.112 | Likely Benign | -2.57 | Deleterious | 0.909 | Possibly Damaging | 0.539 | Possibly Damaging | 3.52 | Benign | 0.00 | Affected | 0.4613 | 0.8203 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||||||||||||
| c.68A>G | D23G 2D  AIThe SynGAP1 missense variant D23G is listed in ClinVar (ID 3644551.0) with an “Uncertain” status and is not reported in gnomAD. 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, 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; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification but leans toward a benign interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | Uncertain | 1 | -2.622 | Likely Benign | 0.684 | Likely Pathogenic | Likely Benign | 0.100 | Likely Benign | -2.45 | Neutral | 0.805 | Possibly Damaging | 0.539 | Possibly Damaging | 3.50 | Benign | 0.00 | Affected | 0.4682 | 0.7632 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||||||||||
| c.68A>T | D23V 2D AIThe SynGAP1 D23V 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. 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 thus unavailable; Foldetta predictions are not provided. Overall, more tools (five) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | -3.244 | Likely Benign | 0.842 | Likely Pathogenic | Ambiguous | 0.137 | Likely Benign | -2.72 | Deleterious | 0.972 | Probably Damaging | 0.804 | Possibly Damaging | 3.48 | Benign | 0.00 | Affected | 0.1515 | 0.8367 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.691T>A | F231I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta’s stability prediction is uncertain and thus not considered evidence. No other tools provide definitive pathogenic or benign conclusions. Based on the preponderance of pathogenic predictions and the lack of contrary evidence, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.827 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.16 | Ambiguous | 0.4 | 1.65 | Ambiguous | 1.41 | Ambiguous | 0.94 | Ambiguous | 0.894 | Likely Pathogenic | -5.01 | Deleterious | 0.759 | Possibly Damaging | 0.328 | Benign | 5.76 | Benign | 0.00 | Affected | 0.2122 | 0.2813 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.691T>G | F231V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates pathogenicity. Taken together, the evidence overwhelmingly points to a pathogenic effect for F231V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.201 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.3 | 2.30 | Destabilizing | 2.23 | Destabilizing | 1.13 | Destabilizing | 0.910 | Likely Pathogenic | -5.90 | Deleterious | 0.759 | Possibly Damaging | 0.328 | Benign | 5.72 | Benign | 0.00 | Affected | 0.2212 | 0.3030 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.692T>C | F231S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -14.655 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.89 | Destabilizing | 0.4 | 4.22 | Destabilizing | 3.56 | Destabilizing | 2.22 | Destabilizing | 0.909 | Likely Pathogenic | -6.92 | Deleterious | 0.608 | Possibly Damaging | 0.205 | Benign | 5.48 | Benign | 0.00 | Affected | 0.4297 | 0.0544 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.692T>G | F231C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools and the high‑accuracy methods, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -13.315 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.26 | Destabilizing | 0.3 | 2.82 | Destabilizing | 2.54 | Destabilizing | 2.04 | Destabilizing | 0.937 | Likely Pathogenic | -6.89 | Deleterious | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.2527 | 0.1612 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.698G>A | C233Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233Y is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are Rosetta and FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic (3 pathogenic vs. 1 benign); and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.893 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 13.15 | Destabilizing | 4.6 | 0.04 | Likely Benign | 6.60 | Destabilizing | 0.71 | Ambiguous | 0.904 | Likely Pathogenic | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 4.29 | 391 | 0.1324 | 0.5284 | 0 | -2 | -3.8 | 60.04 | 248.9 | -63.0 | 0.0 | 0.3 | 0.0 | 0.4 | X | X | Potentially Pathogenic | The introduced residue Tyr233 is located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Ala232) and an α helix (residues Ala236-Val250). Although the thiol group of a cysteine side chain is not a strong hydrogen bond acceptor or donor, it facilitates hydrogen bonding between Cys233 and the backbone carbonyl of Ala232 in the WT simulations. In the variant simulations, the bulky phenol ring of the Tyr233 side chain stacks with the indole ring of the Trp242 side chain. This interaction could alter the tertiary assembly of the β sheet and α helix due to the residue swap. Indeed, in the second replica simulation, the protein structure begins to unfold to accommodate the introduced Tyr233 side chain. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||
| c.698G>T | C233F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include Rosetta, premPS, and FATHMM, whereas the remaining tools—REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Foldetta—predict a pathogenic or likely pathogenic impact. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence supports a pathogenic effect, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.564 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 9.36 | Destabilizing | 3.0 | -0.19 | Likely Benign | 4.59 | Destabilizing | 0.37 | Likely Benign | 0.901 | Likely Pathogenic | -9.79 | Deleterious | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 5.73 | Benign | 0.00 | Affected | 0.1524 | 0.5231 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.699T>G | C233W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233W is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a benign outcome, while Rosetta and premPS are uncertain. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence indicates that C233W is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -17.899 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.72 | Destabilizing | 6.6 | 1.07 | Ambiguous | 7.90 | Destabilizing | 0.54 | Ambiguous | 0.772 | Likely Pathogenic | -9.79 | Deleterious | 0.983 | Probably Damaging | 0.715 | Possibly Damaging | 5.71 | Benign | 0.00 | Affected | 0.1727 | 0.5292 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.69T>A | D23E 2D AIThe SynGAP1 D23E 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, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | -3.329 | Likely Benign | 0.565 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -1.35 | Neutral | 0.643 | Possibly Damaging | 0.417 | Benign | 3.59 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2420 | 0.8363 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.69T>G | D23E 2D AIThe SynGAP1 missense variant D23E is listed in gnomAD (ID 6‑33423478‑T‑G) but has no ClinVar entry. 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 the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence—including the consensus and high‑accuracy tools—points to a benign effect, 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 Benign | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | 6-33423478-T-G | 15 | 9.29e-6 | -3.329 | Likely Benign | 0.565 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -1.35 | Neutral | 0.643 | Possibly Damaging | 0.417 | Benign | 3.59 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2420 | 0.8363 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.6C>A | S2R 2D AIThe SynGAP1 missense variant S2R is present in gnomAD (ID 6‑33420270‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | 6-33420270-C-A | 1 | 6.52e-7 | -3.684 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.070 | Likely Benign | -0.44 | Neutral | 0.117 | Benign | 0.008 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0996 | 0.4503 | -1 | 0 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||
| c.6C>G | S2R 2D AIThe SynGAP1 missense variant S2R 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, polyPhen‑2 HumDiv, polyPhen‑2 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the preponderance of evidence from multiple prediction tools and high‑accuracy methods 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. | Likely Benign | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | -3.684 | Likely Benign | 0.426 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -0.44 | Neutral | 0.117 | Benign | 0.008 | Benign | 4.05 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0996 | 0.4503 | -1 | 0 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.704C>A | S235Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for S235Y, 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 | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -15.842 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 1.8 | 0.43 | Likely Benign | 1.98 | Ambiguous | 0.66 | Ambiguous | 0.887 | Likely Pathogenic | -5.14 | Deleterious | 0.971 | Probably Damaging | 0.641 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | 0.0733 | 0.5269 | -3 | -2 | -0.5 | 76.10 | |||||||||||||||||||||||||||||
| c.704C>G | S235C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas a majority of tools (REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Results from high‑accuracy methods are mixed: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta is uncertain. Because the uncertain predictions are treated as unavailable, the overall evidence still favors 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 | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -11.350 | Likely Pathogenic | 0.800 | Likely Pathogenic | Ambiguous | 1.74 | Ambiguous | 0.1 | 0.42 | Likely Benign | 1.08 | Ambiguous | 0.76 | Ambiguous | 0.878 | Likely Pathogenic | -4.24 | Deleterious | 0.977 | Probably Damaging | 0.620 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | 0.1284 | 0.6015 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.704C>T | S235F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235F is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FATHMM and Rosetta, whereas the majority of other in silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic. Two tools give inconclusive results: Foldetta (protein‑folding stability) and premPS. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta remains uncertain. Overall, the preponderance of evidence from both general and high‑accuracy predictors 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 | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -14.456 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 1.7 | 0.46 | Likely Benign | 1.75 | Ambiguous | 0.56 | Ambiguous | 0.919 | Likely Pathogenic | -5.14 | Deleterious | 0.917 | Possibly Damaging | 0.548 | Possibly Damaging | 5.45 | Benign | 0.00 | Affected | 0.0617 | 0.5393 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.70G>A | V24I 2D  AIThe SynGAP1 missense variant V24I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33423479-G-A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of computational evidence supports a benign impact for V24I, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | Uncertain | 1 | 6-33423479-G-A | 9 | 5.58e-6 | -3.701 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.25 | Neutral | 0.043 | Benign | 0.031 | Benign | 3.96 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0844 | 0.4564 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||
| c.70G>C | V24L 2D  AIThe SynGAP1 missense variant V24L 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 further support a benign interpretation: 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 effect for V24L, 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 | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.590 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.62 | Neutral | 0.043 | Benign | 0.011 | Benign | 3.94 | Benign | 0.00 | Affected | 0.1102 | 0.5226 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.70G>T | V24L 2D AIThe SynGAP1 missense variant V24L 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 further support a benign interpretation: 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 effect for V24L, 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 | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.590 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.62 | Neutral | 0.043 | Benign | 0.011 | Benign | 3.94 | Benign | 0.00 | Affected | 0.1102 | 0.5226 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.713A>G | E238G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238G is reported in gnomAD (variant ID 6‑33435564‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a deleterious effect: the benign‑predicting tool FATHMM is the only one that classifies it as benign, whereas the pathogenic‑predicting tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Pathogenic” call) all predict a harmful impact. Predictions of uncertain status (FoldX, premPS) are treated as unavailable. High‑accuracy assessments reinforce the pathogenic view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the overwhelming agreement among high‑confidence 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 | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | 6-33435564-A-G | 1 | 6.19e-7 | -12.582 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.09 | Ambiguous | 0.2 | 3.42 | Destabilizing | 2.26 | Destabilizing | 0.87 | Ambiguous | 0.889 | Likely Pathogenic | -6.35 | Deleterious | 0.970 | Probably Damaging | 0.607 | Possibly Damaging | 5.39 | Benign | 0.00 | Affected | 3.40 | 14 | 0.3137 | 0.4833 | -2 | 0 | 3.1 | -72.06 | ||||||||||||||||||||||||
| c.713A>T | E238V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E238V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E238V. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -14.329 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.88 | Ambiguous | 0.4 | 0.75 | Ambiguous | 0.82 | Ambiguous | 0.45 | Likely Benign | 0.890 | Likely Pathogenic | -6.35 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.00 | Affected | 0.0848 | 0.6093 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.716G>T | R239I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R239I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS (uncertain), PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—classify the variant as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.170161 | Structured | 0.336504 | Uncertain | 0.854 | 0.319 | 0.000 | -19.414 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.5 | 2.53 | Destabilizing | 3.43 | Destabilizing | 0.83 | Ambiguous | 0.890 | Likely Pathogenic | -7.16 | Deleterious | 0.985 | Probably Damaging | 0.724 | Possibly Damaging | 5.69 | Benign | 0.00 | Affected | 0.1480 | 0.3985 | -2 | -3 | 9.0 | -43.03 | |||||||||||||||||||||||||||||
| c.718G>C | D240H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240H missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are uncertain. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -14.551 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 1.14 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.88 | Ambiguous | 0.19 | Likely Benign | 0.865 | Likely Pathogenic | -6.12 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.78 | Benign | 0.00 | Affected | 0.1223 | 0.5398 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.718G>T | D240Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240Y missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, premPS, and FATHMM; pathogenic predictions come from REVEL, 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 also pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Taken together, the overwhelming majority of reliable predictors indicate a pathogenic effect for D240Y. This conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -16.890 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.29 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.68 | Ambiguous | -0.01 | Likely Benign | 0.899 | Likely Pathogenic | -7.90 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.77 | Benign | 0.00 | Affected | 0.0439 | 0.4932 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.719A>T | D240V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240V missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, FATHMM, and premPS, whereas the majority of algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score—classify the change as pathogenic or 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, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D240V. 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 | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -15.095 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 1.32 | Ambiguous | 0.1 | 0.28 | Likely Benign | 0.80 | Ambiguous | 0.11 | Likely Benign | 0.894 | Likely Pathogenic | -7.94 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 5.82 | Benign | 0.00 | Affected | 0.0610 | 0.4949 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.71T>A | V24E 2D AIThe SynGAP1 missense variant V24E 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, the SGM‑Consensus also indicates Likely Benign, 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 | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -3.397 | Likely Benign | 0.517 | Ambiguous | Likely Benign | 0.171 | Likely Benign | -1.73 | Neutral | 0.198 | Benign | 0.074 | Benign | 3.77 | Benign | 0.00 | Affected | 0.1133 | 0.2415 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||||||||||||
| c.71T>C | V24A 2D  AIThe SynGAP1 missense variant V24A 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 predict benign, while only SIFT predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign impact for V24A. This prediction is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.980 | Likely Benign | 0.299 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.09 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.83 | Benign | 0.00 | Affected | 0.3117 | 0.3350 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||||||||||||
| c.71T>G | V24G 2D AIThe SynGAP1 missense variant V24G is not reported in ClinVar (ClinVar status: not present) 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, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta results are unavailable. 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. | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.673 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -1.67 | Neutral | 0.026 | Benign | 0.049 | Benign | 3.77 | Benign | 0.00 | Affected | 0.2081 | 0.3105 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.724T>A | W242R 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant W242R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess evolutionary conservation and protein function uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Consequently, 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 | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -11.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.85 | Ambiguous | 0.5 | 1.15 | Ambiguous | 1.00 | Ambiguous | 1.34 | Destabilizing | 0.859 | Likely Pathogenic | -12.71 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 3.40 | 14 | 0.4206 | 0.0771 | -3 | 2 | -3.6 | -30.03 | |||||||||||||||||||||||||||
| c.724T>C | W242R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242R is reported in gnomAD (ID 6‑33435575‑T‑C) but has no ClinVar entry. Across the evaluated predictors, every tool that provides a definitive call classifies the substitution as pathogenic: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No predictor reports a benign effect. FoldX, Rosetta, and Foldetta return uncertain results and are treated as unavailable evidence. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, while Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic based on the consensus of pathogenic 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. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | 6-33435575-T-C | 2 | 1.24e-6 | -11.948 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.85 | Ambiguous | 0.5 | 1.15 | Ambiguous | 1.00 | Ambiguous | 1.34 | Destabilizing | 0.858 | Likely Pathogenic | -12.71 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 3.40 | 14 | 0.4206 | 0.0771 | -3 | 2 | -3.6 | -30.03 | ||||||||||||||||||||||||
| c.724T>G | W242G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD, so no population frequency data are available. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the single uncertain call from premPS is treated as unavailable. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the unanimous 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 | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -14.319 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.70 | Destabilizing | 0.3 | 2.48 | Destabilizing | 2.59 | Destabilizing | 0.83 | Ambiguous | 0.883 | Likely Pathogenic | -11.80 | Deleterious | 0.900 | Possibly Damaging | 0.452 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 0.4378 | 0.1851 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.725G>C | W242S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242S, located in the PH domain, is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments further support a harmful impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic,” while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the consensus of available predictions indicates that W242S 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 | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -14.674 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.96 | Ambiguous | 0.2 | 1.97 | Ambiguous | 1.97 | Ambiguous | 0.83 | Ambiguous | 0.797 | Likely Pathogenic | -12.71 | Deleterious | 0.900 | Possibly Damaging | 0.535 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 0.4424 | 0.1418 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||
| c.726G>C | W242C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 W242C missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS, and no tools predict a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as ClinVar has not yet classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -13.117 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.77 | Ambiguous | 0.4 | 1.62 | Ambiguous | 1.70 | Ambiguous | 0.63 | Ambiguous | 0.889 | Likely Pathogenic | -11.80 | Deleterious | 0.999 | Probably Damaging | 0.887 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 0.3626 | 0.1617 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.726G>T | W242C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W242C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS, and no tools predict a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Based on the collective predictions, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as ClinVar has not yet classified the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.328603 | Structured | 0.352582 | Uncertain | 0.847 | 0.341 | 0.000 | -13.117 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 1.77 | Ambiguous | 0.4 | 1.62 | Ambiguous | 1.70 | Ambiguous | 0.63 | Ambiguous | 0.889 | Likely Pathogenic | -11.80 | Deleterious | 0.999 | Probably Damaging | 0.887 | Possibly Damaging | 1.52 | Pathogenic | 0.00 | Affected | 0.3626 | 0.1617 | -8 | -2 | 3.4 | -83.07 | |||||||||||||||||||||||||||||
| c.728T>A | I243N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant I243N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into three groups: benign (FATHMM), pathogenic (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized), and uncertain (FoldX, Rosetta, Foldetta). High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -14.784 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 1.90 | Ambiguous | 0.2 | 1.43 | Ambiguous | 1.67 | Ambiguous | 1.76 | Destabilizing | 0.811 | Likely Pathogenic | -4.46 | Deleterious | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.49 | Benign | 0.00 | Affected | 0.0899 | 0.0212 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.728T>G | I243S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -14.097 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 2.52 | Destabilizing | 0.2 | 2.22 | Destabilizing | 2.37 | Destabilizing | 1.71 | Destabilizing | 0.802 | Likely Pathogenic | -3.55 | Deleterious | 0.995 | Probably Damaging | 0.795 | Possibly Damaging | 5.52 | Benign | 0.00 | Affected | 0.2658 | 0.0600 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.731A>T | E244V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E244V missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. Four tools (FoldX, Rosetta, Foldetta, premPS) returned uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenicity; Foldetta 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 contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -12.118 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.04 | Ambiguous | 0.1 | 1.02 | Ambiguous | 1.03 | Ambiguous | 0.56 | Ambiguous | 0.925 | Likely Pathogenic | -5.90 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.68 | Benign | 0.00 | Affected | 0.0636 | 0.6073 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.733A>T | N245Y 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N245Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a pathogenic majority (3/4). AlphaMissense‑Optimized independently predicts pathogenicity, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. premPS remains 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. Thus, the variant is most likely pathogenic, with no ClinVar entry to contradict this assessment. 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 | -12.476 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | -0.36 | Likely Benign | 0.1 | 0.11 | Likely Benign | -0.13 | Likely Benign | 0.59 | Ambiguous | 0.855 | Likely Pathogenic | -6.68 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.86 | Benign | 0.00 | Affected | 0.0706 | 0.6771 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.734A>T | N245I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245I 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 Rosetta, Foldetta, and FATHMM, while those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict 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 | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -14.527 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | -0.56 | Ambiguous | 0.1 | 0.04 | Likely Benign | -0.26 | Likely Benign | 0.60 | Ambiguous | 0.831 | Likely Pathogenic | -7.46 | Deleterious | 0.995 | Probably Damaging | 0.832 | Possibly Damaging | 5.88 | Benign | 0.00 | Affected | 0.0672 | 0.6999 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.737T>A | L246Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246Q missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact; Rosetta is uncertain and is not grouped. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -15.420 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.3 | 1.79 | Ambiguous | 2.31 | Destabilizing | 1.69 | Destabilizing | 0.921 | Likely Pathogenic | -5.43 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.1092 | 0.0758 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.737T>C | L246P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L246P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: the single benign prediction comes from FATHMM, while all other evaluated algorithms (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -16.581 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 6.42 | Destabilizing | 0.3 | 8.72 | Destabilizing | 7.57 | Destabilizing | 1.79 | Destabilizing | 0.944 | Likely Pathogenic | -6.30 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.3731 | 0.1582 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.737T>G | L246R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L246R missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.472492 | Structured | 0.302312 | Uncertain | 0.859 | 0.364 | 0.000 | -13.849 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.94 | Destabilizing | 0.8 | 2.77 | Destabilizing | 3.36 | Destabilizing | 1.72 | Destabilizing | 0.925 | Likely Pathogenic | -5.43 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.67 | Benign | 0.00 | Affected | 0.1266 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.73C>G | R25G 2D AIThe SynGAP1 missense variant R25G is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. When high‑accuracy tools are considered separately, AlphaMissense‑Optimized predicts a benign effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome, and Foldetta data are unavailable. Overall, the majority of robust predictors lean toward a benign interpretation. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | -3.533 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.69 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 0.3621 | 0.3572 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.73C>T | R25W 2D AIThe SynGAP1 missense variant R25W is listed in ClinVar with an “Uncertain” status (ClinVar ID 2993054.0) and is present in gnomAD (ID 6‑33423482‑C‑T). 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, and SIFT; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | Uncertain | 2 | 6-33423482-C-T | 6 | 3.72e-6 | -5.133 | Likely Benign | 0.549 | Ambiguous | Likely Benign | 0.158 | Likely Benign | -1.60 | Neutral | 0.994 | Probably Damaging | 0.919 | Probably Damaging | 3.92 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1224 | 0.3938 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.742C>G | R248G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | -13.413 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.23 | Destabilizing | 0.7 | 2.67 | Destabilizing | 2.45 | Destabilizing | 1.33 | Destabilizing | 0.770 | Likely Pathogenic | -6.07 | Deleterious | 0.958 | Probably Damaging | 0.502 | Possibly Damaging | 5.70 | Benign | 0.00 | Affected | 0.3011 | 0.3385 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.742C>T | R248W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R248W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Rosetta, Foldetta, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results from FoldX and premPS are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. Overall, the majority of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | Uncertain | 1 | -11.647 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.17 | Ambiguous | 0.3 | -0.20 | Likely Benign | 0.49 | Likely Benign | 0.89 | Ambiguous | 0.699 | Likely Pathogenic | -6.98 | Deleterious | 1.000 | Probably Damaging | 0.948 | Probably Damaging | 5.62 | Benign | 0.00 | Affected | 3.41 | 14 | 0.1124 | 0.4037 | 2 | -3 | 3.6 | 30.03 | 266.4 | 42.3 | 0.0 | 0.0 | 0.3 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg248, located on an α helix (res. Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the indole group of Trp248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Instead, in the variant simulations, the indole ring of Trp248 stacks against Pro252, which makes a turn after the α helix. | ||||||||||||||||
| c.743G>C | R248P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R248P is listed in ClinVar as Pathogenic (ClinVar ID 1065478.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a destabilizing, pathogenic effect. Based on the overwhelming consensus of pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic, which aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.267126 | Uncertain | 0.781 | 0.346 | 0.250 | Likely Pathogenic | 1 | -10.751 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.09 | Destabilizing | 0.6 | 8.87 | Destabilizing | 5.98 | Destabilizing | 1.21 | Destabilizing | 0.848 | Likely Pathogenic | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.878 | Possibly Damaging | 5.64 | Benign | 0.00 | Affected | 3.41 | 14 | 0.1943 | 0.4528 | 0 | -2 | 2.9 | -59.07 | 223.8 | 126.6 | 0.0 | 0.0 | -0.2 | 0.1 | X | X | Potentially Pathogenic | The guanidinium group of Arg248, located on an α helix (residues Ala236-Val250), forms two very stable salt bridges with Asp255 (from a short α helical section, res. Lys254-Asn256) and Glu244 (from a nearby loop) in the WT simulations. In the variant simulations, the pyrrolidine side chain of Pro248 cannot form any salt bridges, which could negatively affect the tertiary structure assembly of the PH domain. Additionally, Pro248 lacks a free amide group needed for hydrogen bonding with the backbone carbonyl group of Asn245, disrupting the continuity of the α helix. | |||||||||||||||
| c.749T>A | V250E 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant V250E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, whereas the remaining 12 tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction or stability result is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -15.723 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.85 | Ambiguous | 0.1 | 3.34 | Destabilizing | 2.60 | Destabilizing | 2.01 | Destabilizing | 0.906 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.74 | Benign | 0.00 | Affected | 0.0787 | 0.1564 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.749T>G | V250G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default, while only FATHMM predicts a benign outcome. Uncertain results are reported by FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, AlphaMissense‑Optimized remains uncertain, and Foldetta is pathogenic. Taken together, the overwhelming majority of evidence indicates a pathogenic effect. This conclusion is consistent with the absence of a ClinVar classification; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.255 | Likely Pathogenic | 0.917 | Likely Pathogenic | Ambiguous | 1.65 | Ambiguous | 0.3 | 3.18 | Destabilizing | 2.42 | Destabilizing | 2.08 | Destabilizing | 0.900 | Likely Pathogenic | -5.90 | Deleterious | 0.879 | Possibly Damaging | 0.997 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | 0.1884 | 0.1996 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.74G>A | R25Q 2D AIThe SynGAP1 missense variant R25Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423483‑G‑A). 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). Tools that predict a pathogenic effect are 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 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 | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | Uncertain | 1 | 6-33423483-G-A | 15 | 9.29e-6 | -4.126 | Likely Benign | 0.212 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.70 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3447 | 0.2566 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.74G>C | R25P 2D AIThe SynGAP1 missense variant R25P 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 polyPhen‑2 (HumDiv and HumVar) and SIFT uniformly predict a pathogenic outcome. AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | -3.394 | Likely Benign | 0.424 | Ambiguous | Likely Benign | 0.155 | Likely Benign | -1.56 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 3.94 | Benign | 0.00 | Affected | 0.2217 | 0.4571 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.74G>T | R25L 2D AIThe SynGAP1 missense variant R25L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight a benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta data are missing. Taken together, the majority of robust predictors and the consensus analysis support a benign classification for R25L. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.461924 | Structured | 0.438941 | Uncertain | 0.373 | 0.890 | 0.375 | -3.443 | Likely Benign | 0.484 | Ambiguous | Likely Benign | 0.121 | Likely Benign | -1.59 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 0.2045 | 0.4792 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.755C>A | P252H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252H missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. No other high‑confidence stability predictions are available. Overall, the preponderance of evidence indicates that P252H is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -11.991 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.06 | Ambiguous | 0.2 | 1.96 | Ambiguous | 1.51 | Ambiguous | 0.82 | Ambiguous | 0.845 | Likely Pathogenic | -8.27 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.1592 | 0.4128 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.755C>G | P252R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P252R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Computational predictors that classify the variant as benign are FoldX and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. Predictions that are inconclusive are Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; Foldetta remains uncertain. Overall, the preponderance of evidence indicates that P252R is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -14.648 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 1.23 | Ambiguous | 0.82 | Ambiguous | 0.81 | Ambiguous | 0.890 | Likely Pathogenic | -8.27 | Deleterious | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 5.80 | Benign | 0.00 | Affected | 0.1413 | 0.2848 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.755C>T | P252L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P252L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign are premPS and FATHMM, while the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic effect. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore do not contribute to the overall assessment. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.461924 | Structured | 0.211606 | Uncertain | 0.753 | 0.304 | 0.250 | -10.181 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.93 | Ambiguous | 0.0 | 1.56 | Ambiguous | 1.25 | Ambiguous | 0.47 | Likely Benign | 0.794 | Likely Pathogenic | -9.19 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 5.81 | Benign | 0.00 | Affected | 0.2027 | 0.6475 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.761A>T | K254M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign predictions come from FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions are reported by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight the conflict: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools and the high‑accuracy consensus lean toward a pathogenic effect, and this assessment does not contradict ClinVar status, which currently has no entry for it. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -12.832 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | -0.35 | Likely Benign | 0.5 | 0.48 | Likely Benign | 0.07 | Likely Benign | 0.23 | Likely Benign | 0.864 | Likely Pathogenic | -5.08 | Deleterious | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 5.78 | Benign | 0.00 | Affected | 0.1073 | 0.3562 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.763G>C | D255H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of the available predictions points to a pathogenic effect for D255H, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -14.645 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.2 | 1.17 | Ambiguous | 1.45 | Ambiguous | 0.44 | Likely Benign | 0.808 | Likely Pathogenic | -5.93 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.1447 | 0.5211 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||
| c.763G>T | D255Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255Y is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions from FoldX, Rosetta, and Foldetta are uncertain and therefore not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as Uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -13.180 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.25 | Ambiguous | 0.2 | 0.96 | Ambiguous | 1.11 | Ambiguous | 0.13 | Likely Benign | 0.832 | Likely Pathogenic | -7.77 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 5.73 | Benign | 0.00 | Affected | 0.0464 | 0.5178 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||
| c.764A>T | D255V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, while pathogenic predictions are made by SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by FoldX, Rosetta, and Foldetta. High‑accuracy methods reinforce the pathogenic interpretation: AlphaMissense‑Optimized predicts Pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains Uncertain. Overall, the consensus of available predictions points to a pathogenic effect for D255V, and this conclusion is consistent with the lack of ClinVar annotation (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -13.575 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 1.76 | Ambiguous | 0.2 | 1.07 | Ambiguous | 1.42 | Ambiguous | 0.16 | Likely Benign | 0.895 | Likely Pathogenic | -7.77 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.75 | Benign | 0.00 | Affected | 0.0684 | 0.5162 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||
| c.766A>T | N256Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256Y is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM, whereas the majority of tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—label it pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the preponderance of evidence from standard predictors and the two high‑accuracy pathogenic calls suggests that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -10.881 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.17 | Likely Benign | 0.2 | -0.80 | Ambiguous | -0.32 | Likely Benign | 0.30 | Likely Benign | 0.868 | Likely Pathogenic | -6.85 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.83 | Benign | 0.00 | Affected | 0.0493 | 0.5881 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.767A>T | N256I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, premPS, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -14.050 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.64 | Ambiguous | 0.4 | 0.45 | Likely Benign | 0.55 | Ambiguous | 0.31 | Likely Benign | 0.849 | Likely Pathogenic | -7.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.87 | Benign | 0.00 | Affected | 0.0596 | 0.6260 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.76G>A | G26R 2D  AIThe SynGAP1 missense variant G26R is listed in ClinVar as a benign alteration (ClinVar ID 1521495.0) and is present in the gnomAD database (gnomAD ID 6‑33423485‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote from 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; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of computational evidence supports a benign impact, aligning with the ClinVar designation and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | Benign | 1 | 6-33423485-G-A | 3 | 1.86e-6 | -2.946 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -2.22 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1097 | 0.4407 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||
| c.76G>C | G26R 2D AIThe SynGAP1 missense variant G26R 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 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, is classified as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of the four high‑accuracy tools) also yields 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—including the high‑accuracy consensus—indicates that G26R is most likely benign, 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 Benign | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | -2.946 | Likely Benign | 0.678 | Likely Pathogenic | Likely Benign | 0.189 | Likely Benign | -2.22 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.87 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1097 | 0.4407 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||
| c.772C>T | R258C 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 R258C missense variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437677‑C‑T). Prediction tools that agree on a benign effect include only FATHMM. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—indicate a pathogenic or likely pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.295083 | Structured | 0.293667 | Uncertain | 0.894 | 0.260 | 0.250 | Uncertain | 1 | 6-33437677-C-T | 1 | 6.20e-7 | -10.285 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 1.17 | Ambiguous | 0.4 | 1.76 | Ambiguous | 1.47 | Ambiguous | 0.87 | Ambiguous | 0.771 | Likely Pathogenic | -6.79 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 5.77 | Benign | 0.00 | Affected | 3.39 | 15 | 0.3307 | 0.3411 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| c.775C>G | R259G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining 13 tools—including SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The high‑accuracy subset reinforces this assessment: 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. Rosetta alone is uncertain and is treated as unavailable. Overall, the consensus of available predictions indicates that R259G 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 | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | -15.389 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.17 | Destabilizing | 0.6 | 1.53 | Ambiguous | 2.35 | Destabilizing | 1.14 | Destabilizing | 0.762 | Likely Pathogenic | -6.43 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.78 | Benign | 0.00 | Affected | 0.3342 | 0.4139 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.775C>T | R259W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R259W is listed in ClinVar with an uncertain significance (ClinVar ID 2014570.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, remains inconclusive. Overall, the preponderance of evidence indicates that R259W is most likely pathogenic, a conclusion that does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | Uncertain | 1 | -12.186 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.95 | Ambiguous | 0.8 | 0.51 | Ambiguous | 1.23 | Ambiguous | 0.51 | Ambiguous | 0.691 | Likely Pathogenic | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 3.39 | 15 | 0.1221 | 0.4269 | 2 | -3 | 3.6 | 30.03 | 254.0 | 40.0 | 0.2 | 0.2 | 0.2 | 0.4 | X | X | X | Potentially Pathogenic | The guanidinium group of Arg259, located at the beginning of an anti-parallel β sheet strand (res. Arg259-Arg272), forms salt bridges with the carboxylate groups of Asp684 at the end of an α helix (res. Ile683-Gln702, GAP domain) and Asp261 on the same β strand. The Arg259 side chain also frequently forms hydrogen bonds with the backbone carbonyl groups of Ser257, Asn256, and Asp255. In the variant simulations, the indole ring of the Trp259 side chain cannot form salt bridges or maintain hydrogen bonding with the carboxylate group of Asp684 or other nearby residues. Notably, the amino group of the Lys254 side chain maintains a salt bridge with Asp684 and Glu244 throughout the variant simulations, while it forms a cation-π bond with the indole ring of Trp259 in the variant. This salt bridge is not maintained in the WT simulations. Additionally, the partially or loosely α helical conformation of a lysine-containing loop (res. Lys251-Ser257), which extends to a nearby α helix (res. Met414-Asn426), could be stabilized due to the residue swap. Moreover, the bulky size of the Trp259 side chain requires nearby residues to adjust their positioning to accommodate the introduced residue, weakening the tertiary structure assembly between the C2, PH, and GAP domains. The residue swap potentially causes more severe effects during protein folding or for the SynGAP-membrane interaction than the solvent-only simulations imply. | ||||||||||||||
| c.776G>C | R259P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods further support this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | -14.876 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.34 | Destabilizing | 1.6 | 3.78 | Destabilizing | 5.06 | Destabilizing | 1.16 | Destabilizing | 0.902 | Likely Pathogenic | -6.43 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.84 | Benign | 0.00 | Affected | 0.2051 | 0.5249 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.776G>T | R259L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R259L is not reported in ClinVar and is absent from gnomAD. Among the available in‑silico predictors, the benign‑predicted tools are Rosetta and FATHMM, while the pathogenic‑predicted tools include SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Foldetta and premPS are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of predictions support a pathogenic effect, 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 | 0.222385 | Structured | 0.338208 | Uncertain | 0.885 | 0.255 | 0.250 | -14.185 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.84 | Destabilizing | 1.1 | 0.16 | Likely Benign | 1.50 | Ambiguous | 0.64 | Ambiguous | 0.894 | Likely Pathogenic | -6.43 | Deleterious | 0.997 | Probably Damaging | 0.987 | Probably Damaging | 5.87 | Benign | 0.00 | Affected | 0.1934 | 0.5499 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.779T>G | V260G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized, while the majority of tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. FoldX, Rosetta, and Foldetta are uncertain and therefore not considered evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (3 pathogenic vs. 1 benign). Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V260G, 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 | 0.254060 | Structured | 0.382651 | Uncertain | 0.888 | 0.259 | 0.250 | -9.300 | Likely Pathogenic | 0.644 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.3 | 1.86 | Ambiguous | 1.43 | Ambiguous | 1.40 | Destabilizing | 0.817 | Likely Pathogenic | -4.20 | Deleterious | 0.991 | Probably Damaging | 0.999 | Probably Damaging | 5.76 | Benign | 0.00 | Affected | 0.1844 | 0.1949 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.77G>A | G26E 2D  AIThe SynGAP1 missense variant G26E is not reported in ClinVar and is absent from 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, polyPhen‑2 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 combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | -3.966 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.199 | Likely Benign | -2.08 | Neutral | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 3.90 | Benign | 0.00 | Affected | 0.1623 | 0.4238 | 0 | -2 | -3.1 | 72.06 | |||||||||||||||||||||||||||||||||||||||
| c.77G>C | G26A 2D  AIThe SynGAP1 missense variant G26A 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, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G26A, 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 | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | -3.308 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.25 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 4.02 | Benign | 0.00 | Affected | 0.4093 | 0.5251 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.77G>T | G26V 2D AIThe SynGAP1 missense variant G26V is reported in gnomAD (variant ID 6‑33423486‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: the benign‑predicted set includes REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the pathogenic‑predicted set contains polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” No Foldetta stability result is available, so it does not influence the conclusion. Overall, the majority of evidence points to a benign effect for G26V, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | 6-33423486-G-T | 1 | 6.20e-7 | -3.499 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -2.34 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 3.89 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1344 | 0.4333 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||
| c.791T>A | L264Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264Q is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | Uncertain | 1 | -15.729 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.43 | Destabilizing | 0.1 | 2.41 | Destabilizing | 2.92 | Destabilizing | 2.48 | Destabilizing | 0.678 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 3.38 | 18 | 0.0942 | 0.0558 | -2 | -2 | -7.3 | 14.97 | 254.7 | -7.6 | 0.0 | 0.0 | 0.0 | 0.3 | X | X | X | Potentially Pathogenic | The iso-butyl branched hydrocarbon side chain of Leu264, located at the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Leu266, Phe314, Leu317, and Leu323 in the WT simulations. In the variant simulations, the hydrophilic carboxamide group of the Gln264 side chain is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxamide group of Gln264 forms hydrogen bonds with the backbone amide groups of Arg405 and Lys256 in the β sheet and the carbonyl group of Val350 in an α helical section of a nearby loop (res. Pro359-Phe358). The residue swap disrupts the packing of the C2 domain, which could adversely affect the C2 domain structure during folding. This disruption could potentially weaken the stability of the SynGAP-membrane association. | ||||||||||||||
| c.791T>C | L264P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset reports a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, a conclusion that contradicts the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | Uncertain | 1 | -12.285 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.73 | Destabilizing | 0.3 | 6.57 | Destabilizing | 6.15 | Destabilizing | 2.65 | Destabilizing | 0.767 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 0.3239 | 0.1053 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||
| c.791T>G | L264R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L264R is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments are consistent: 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. Consequently, the variant is most likely pathogenic, and this prediction 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 | 0.185198 | Structured | 0.323473 | Uncertain | 0.939 | 0.264 | 0.000 | -16.976 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.25 | Destabilizing | 0.3 | 3.37 | Destabilizing | 3.81 | Destabilizing | 2.28 | Destabilizing | 0.742 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 0.1132 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.797T>A | L266Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L266Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect: none. Tools that agree on a pathogenic effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The only tool with an uncertain outcome is Rosetta. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -16.672 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.92 | Destabilizing | 0.1 | 1.49 | Ambiguous | 2.21 | Destabilizing | 2.21 | Destabilizing | 0.563 | Likely Pathogenic | -5.25 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0815 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.797T>C | L266P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. No conflicting benign evidence is present. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -15.752 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.08 | Destabilizing | 0.1 | 4.02 | Destabilizing | 5.55 | Destabilizing | 2.31 | Destabilizing | 0.654 | Likely Pathogenic | -6.06 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.3158 | 0.1021 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.797T>G | L266R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -17.131 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.97 | Destabilizing | 0.2 | 2.76 | Destabilizing | 3.37 | Destabilizing | 2.04 | Destabilizing | 0.574 | Likely Pathogenic | -5.32 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.1059 | 0.0558 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.79C>A | P27T 2D AIThe SynGAP1 missense variant P27T 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‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including high‑accuracy tools, points to a benign effect for P27T, 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 | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -3.612 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -2.07 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 3.85 | Benign | 0.00 | Affected | 0.2430 | 0.5923 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.79C>G | P27A 2D AIThe SynGAP1 missense variant P27A 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‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence, including high‑accuracy tools, points to a benign effect for P27A, 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 | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -3.409 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -1.98 | Neutral | 0.805 | Possibly Damaging | 0.857 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.4041 | 0.5219 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.79C>T | P27S 2D AIThe SynGAP1 missense variant P27S is reported in gnomAD (ID 6‑33423488‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (derived from the majority of these high‑accuracy predictors) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign. Foldetta stability analysis is unavailable. Overall, the preponderance of evidence indicates that P27S is most likely benign, and this assessment does not contradict any ClinVar classification, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | 6-33423488-C-T | 1 | 6.20e-7 | -2.891 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -2.01 | Neutral | 0.909 | Possibly Damaging | 0.901 | Possibly Damaging | 3.91 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3916 | 0.5443 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.7A>G | R3G 2D AIThe SynGAP1 missense variant R3G is reported in gnomAD (ID 6‑33420271‑A‑G) but has no ClinVar entry. 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. Only SIFT predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign; Foldetta results are unavailable. Taken together, the preponderance of evidence points to a benign impact. 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 | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | 6-33420271-A-G | -3.093 | Likely Benign | 0.160 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.20 | Neutral | 0.115 | Benign | 0.018 | Benign | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3559 | 0.4114 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||
| c.7A>T | R3W 2D AIThe SynGAP1 missense variant R3W 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, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for R3W, 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 | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -5.023 | Likely Benign | 0.591 | Likely Pathogenic | Likely Benign | 0.122 | Likely Benign | 0.08 | Neutral | 0.962 | Probably Damaging | 0.363 | Benign | 3.94 | Benign | 0.00 | Affected | 0.1407 | 0.4634 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.802A>T | I268F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while the SGM‑Consensus score is “Likely Pathogenic.” No tool in the dataset predicts a benign outcome; only Rosetta and Foldetta are uncertain. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) remains uncertain. Overall, the consensus of available predictions strongly supports a pathogenic classification for I268F, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -11.426 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 2.85 | Destabilizing | 0.7 | 0.59 | Ambiguous | 1.72 | Ambiguous | 1.00 | Destabilizing | 0.685 | Likely Pathogenic | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0427 | 0.2158 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.803T>A | I268N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -13.664 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.48 | Destabilizing | 0.1 | 3.17 | Destabilizing | 3.33 | Destabilizing | 2.21 | Destabilizing | 0.812 | Likely Pathogenic | -6.26 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.0708 | 0.0142 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.803T>C | I268T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268T is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on pathogenicity include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) indicates a destabilizing, pathogenic effect. All available predictions are concordant and point to a deleterious impact. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -10.753 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.44 | Destabilizing | 0.1 | 3.19 | Destabilizing | 3.32 | Destabilizing | 1.93 | Destabilizing | 0.828 | Likely Pathogenic | -4.24 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0882 | 0.0638 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.803T>G | I268S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -13.032 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.93 | Destabilizing | 0.1 | 4.54 | Destabilizing | 4.74 | Destabilizing | 2.10 | Destabilizing | 0.841 | Likely Pathogenic | -5.34 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.2037 | 0.0530 | -1 | -2 | -5.3 | -26.08 | |||||||||||||||||||||||||||||
| c.809A>G | E270G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Pathogenic. Rosetta also predicts pathogenicity, while FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. No tool predicts a benign effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -13.759 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 1.23 | Ambiguous | 0.2 | 2.37 | Destabilizing | 1.80 | Ambiguous | 0.61 | Ambiguous | 0.576 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.63 | Pathogenic | 0.00 | Affected | 0.3254 | 0.3876 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.809A>T | E270V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E270V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly classify the substitution as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return pathogenic scores. No tool predicts a benign effect. Uncertain results are reported only by FoldX, Rosetta, Foldetta, and premPS, which are not considered evidence for or against pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic”; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Overall, the consensus of available predictions indicates that E270V 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 | 0.144935 | Structured | 0.382573 | Uncertain | 0.938 | 0.231 | 0.125 | -15.969 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.38 | Ambiguous | 0.6 | 1.88 | Ambiguous | 1.63 | Ambiguous | -0.52 | Ambiguous | 0.574 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.53 | Pathogenic | 0.00 | Affected | 0.0672 | 0.4498 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.80C>A | P27H 2D AIThe SynGAP1 missense variant P27H 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‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: 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 P27H, 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 | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -4.116 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -2.46 | Neutral | 0.992 | Probably Damaging | 0.977 | Probably Damaging | 3.79 | Benign | 0.00 | Affected | 0.2384 | 0.5290 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.80C>G | P27R 2D AIThe SynGAP1 missense variant P27R 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 returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for P27R, 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 | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -3.260 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -2.28 | Neutral | 0.972 | Probably Damaging | 0.954 | Probably Damaging | 3.82 | Benign | 0.00 | Affected | 0.1744 | 0.4203 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.80C>T | P27L 2D AIThe SynGAP1 missense variant P27L 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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. The predictions do 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 | 0.517562 | Disordered | 0.437871 | Uncertain | 0.430 | 0.881 | 0.375 | -3.297 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.174 | Likely Benign | -2.59 | Deleterious | 0.909 | Possibly Damaging | 0.927 | Probably Damaging | 3.82 | Benign | 0.00 | Affected | 0.2684 | 0.6161 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.812C>A | A271D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A271D is listed in ClinVar as Pathogenic (ClinVar ID 2019732.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.413873 | Uncertain | 0.939 | 0.220 | 0.125 | Pathogenic | 1 | -18.590 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.71 | Destabilizing | 0.4 | 2.67 | Destabilizing | 3.69 | Destabilizing | 1.59 | Destabilizing | 0.706 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.62 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.1565 | 0.1541 | 0 | -2 | -5.3 | 44.01 | 226.2 | -63.4 | 0.0 | 0.0 | 0.9 | 0.1 | X | X | X | X | Potentially Pathogenic | The methyl group of Ala271, located near the end of an anti-parallel β sheet strand (res. Arg259-Arg272), packs against multiple hydrophobic residues such as Val400, Val306, and Leu274 in the WT simulations. In the variant simulations, the carboxylate group of Asp271 is not suitable for the hydrophobic niche, causing the hydrophobic residues to make room for the swapped residue. Additionally, the carboxylate group of the Asp271 side chain forms hydrogen bonds with the backbone amide groups of Arg272 and Ala399 in the β sheet, or even forms a salt bridge with the amino group of the Lys394 side chain. This directly affects the integrity of the anti-parallel β sheet at the end. In short, the residue swap disrupts the C2 domain packing during folding, which could weaken the stability of the SynGAP-membrane association. | |||||||||||||
| 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.821T>A | L274Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274Q is reported in ClinVar with an uncertain significance (ClinVar ID 1810279.0) and is not found in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while Rosetta remains inconclusive. No tool predicts a benign outcome. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.066181 | Structured | 0.377483 | Uncertain | 0.866 | 0.195 | 0.250 | Uncertain | 1 | -15.518 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.54 | Destabilizing | 0.3 | 1.74 | Ambiguous | 2.14 | Destabilizing | 1.97 | Destabilizing | 0.774 | Likely Pathogenic | -5.42 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.00 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.1128 | 0.0688 | -2 | -2 | -7.3 | 14.97 | 245.9 | 1.8 | 0.0 | 0.0 | 0.1 | 0.2 | X | X | X | Potentially Pathogenic | The aliphatic side chain of Leu274, located in a β hairpin loop (res. Glu273-Lys278) connecting two anti-parallel β sheet strands, packs against multiple hydrophobic residues facing the β sheet (e.g., Ala271, Leu327, Tyr280, Val306). The hydrophilic carboxamide group of the Gln274 side chain is not suitable for this hydrophobic niche, causing nearby residues to adjust to make room for the hydrophilic glutamine. Additionally, a new hydrogen bond forms with the backbone carboxyl group of Arg272 in another β strand (res. Glu273-Arg259).As a result, the backbone amide group of Ala399 and the carbonyl group of Arg272, which connect two β strands at the β sheet end, form fewer hydrogen bonds in the variant than in the WT simulations. Although no major secondary structure disruption is observed in the variant simulations, the residue swap could profoundly affect the C2 domain folding, as the hydrophobic packing of Leu274 is crucial for maintaining the loop's contact with the rest of the C2 domain. Lastly, because the Leu274-containing loop faces the membrane surface, the residue swap could also negatively impact the SynGAP-membrane association. | ||||||||||||||
| c.821T>C | L274P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool in the dataset predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous 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 | C2 | 0.066181 | Structured | 0.377483 | Uncertain | 0.866 | 0.195 | 0.250 | -14.667 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 5.62 | Destabilizing | 1.5 | 4.49 | Destabilizing | 5.06 | Destabilizing | 1.66 | Destabilizing | 0.804 | Likely Pathogenic | -6.30 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.00 | Pathogenic | 0.00 | Affected | 0.3535 | 0.0625 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.821T>G | L274R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L274R is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. All available predictions and stability analyses are concordant and indicate a likely pathogenic impact. Thus, based on the current computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.066181 | Structured | 0.377483 | Uncertain | 0.866 | 0.195 | 0.250 | -17.691 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.61 | Destabilizing | 0.8 | 3.15 | Destabilizing | 3.38 | Destabilizing | 1.56 | Destabilizing | 0.807 | Likely Pathogenic | -5.45 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.00 | Pathogenic | 0.00 | Affected | 0.1404 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| 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.827C>A | P276H 2D 3DClick to see structure in 3D Viewer AISynGAP1 P276H is reported in gnomAD (ID 6‑33437732‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all classify the variant as pathogenic, while only AlphaMissense‑Optimized predicts a benign outcome. Uncertain results are provided by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic 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 Pathogenic | C2 | 0.037156 | Structured | 0.338937 | Uncertain | 0.724 | 0.230 | 0.250 | 6-33437732-C-A | 1 | 6.20e-7 | -10.469 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | 1.98 | Ambiguous | 0.1 | 1.09 | Ambiguous | 1.54 | Ambiguous | 0.85 | Ambiguous | 0.534 | Likely Pathogenic | -4.80 | Deleterious | 1.000 | Probably Damaging | 0.961 | Probably Damaging | 1.84 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.1739 | 0.3439 | -2 | 0 | -1.6 | 40.02 | ||||||||||||||||||||||||
| c.82T>C | S28P 2D AIThe SynGAP1 missense variant S28P is listed in ClinVar (ID 1500161.0) with an uncertain significance designation and is not reported in 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 predict benign, while only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the collective evidence points to a benign classification for S28P, 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 Benign | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | Uncertain | 1 | -3.309 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 1.37 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.53 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2432 | 0.5499 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.830A>T | K277M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K277M missense variant is not reported in ClinVar and has no entries in gnomAD. Prediction tools cluster into two groups: benign predictions come from FoldX and premPS, while the majority of tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—label the change as pathogenic. High‑accuracy methods reinforce this trend: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.061840 | Structured | 0.321811 | Uncertain | 0.649 | 0.247 | 0.250 | -13.918 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.0 | 1.14 | Ambiguous | 0.66 | Ambiguous | 0.15 | Likely Benign | 0.712 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.80 | Pathogenic | 0.00 | Affected | 0.0945 | 0.2584 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.835C>T | R279W 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R279W is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a strong bias toward pathogenicity: benign predictions are limited to REVEL, whereas pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive include Foldetta, AlphaMissense‑Optimized, Rosetta, and premPS. 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 is uncertain. Overall, the preponderance of evidence indicates that R279W is most likely pathogenic, a conclusion that contradicts the current ClinVar uncertain status. 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 | Conflicting | 2 | -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.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.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.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.848A>T | E283V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E283V missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are FoldX and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools give inconclusive results: Rosetta (Uncertain) and Foldetta (Uncertain). High‑accuracy methods specifically indicate that AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely pathogenic, whereas Foldetta’s stability assessment is uncertain. Taken together, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic effect for E283V. This conclusion is consistent with the absence 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 | 0.098513 | Structured | 0.358602 | Uncertain | 0.950 | 0.249 | 0.000 | -13.602 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.2 | 0.56 | Ambiguous | 0.50 | Ambiguous | 0.36 | Likely Benign | 0.558 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.83 | Pathogenic | 0.00 | Affected | 0.0874 | 0.6011 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.851T>A | L284H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L284H is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a pathogenic impact. Based on the unanimous 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 | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -16.581 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.26 | Destabilizing | 0.1 | 3.06 | Destabilizing | 3.16 | Destabilizing | 2.57 | Destabilizing | 0.772 | Likely Pathogenic | -6.22 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 0.0954 | 0.0726 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.851T>C | L284P 2D AIThe SynGAP1 missense variant L284P is listed in ClinVar as Pathogenic (ClinVar ID 3344808.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | Likely Pathogenic | 1 | -15.588 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.83 | Destabilizing | 0.2 | 5.81 | Destabilizing | 5.82 | Destabilizing | 1.89 | Destabilizing | 0.794 | Likely Pathogenic | -6.17 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.64 | Pathogenic | 0.00 | Affected | 0.3540 | 0.1021 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||
| c.851T>G | L284R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L284R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. With all available evidence pointing to a damaging effect and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -17.698 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.05 | Destabilizing | 0.5 | 4.29 | Destabilizing | 4.67 | Destabilizing | 2.14 | Destabilizing | 0.797 | Likely Pathogenic | -5.38 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.65 | Pathogenic | 0.00 | Affected | 0.1175 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.857T>A | L286Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L286Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect. No tool predicts a benign outcome. Two tools, Rosetta and Foldetta, return uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.122885 | Structured | 0.385647 | Uncertain | 0.932 | 0.260 | 0.000 | -13.056 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.37 | Destabilizing | 0.3 | 1.42 | Ambiguous | 1.90 | Ambiguous | 2.06 | Destabilizing | 0.852 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.48 | Pathogenic | 0.00 | Affected | 0.1123 | 0.0958 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.857T>C | L286P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L286P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the consensus of all available 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 | 0.122885 | Structured | 0.385647 | Uncertain | 0.932 | 0.260 | 0.000 | -14.982 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.43 | Destabilizing | 0.9 | 6.38 | Destabilizing | 5.91 | Destabilizing | 2.10 | Destabilizing | 0.878 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.47 | Pathogenic | 0.00 | Affected | 0.3719 | 0.1182 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.857T>G | L286R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L286R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while Rosetta remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus (majority vote) is likely pathogenic; and Foldetta, which integrates FoldX‑MD (pathogenic) and Rosetta (uncertain), reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.122885 | Structured | 0.385647 | Uncertain | 0.932 | 0.260 | 0.000 | -15.563 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.90 | Destabilizing | 0.3 | 1.80 | Ambiguous | 2.35 | Destabilizing | 1.97 | Destabilizing | 0.868 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.49 | Pathogenic | 0.00 | Affected | 0.1370 | 0.0600 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.859G>C | D287H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D287H missense variant is listed in ClinVar as Pathogenic (ClinVar ID 1700054.0) and is not reported in gnomAD. Functional prediction tools that assess the variant’s effect on protein function largely agree on a deleterious outcome. Benign predictions come from FoldX, Rosetta, and Foldetta, whereas pathogenic predictions are reported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS remains uncertain. High‑accuracy assessments further support a pathogenic classification: 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, predicts benign. Overall, the majority of evidence points to a pathogenic effect, consistent with the ClinVar designation and not contradicting it. 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 | Likely Pathogenic | 1 | -14.518 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.48 | Likely Benign | 0.3 | 0.32 | Likely Benign | 0.40 | Likely Benign | 0.63 | Ambiguous | 0.589 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 3.38 | 23 | 0.1620 | 0.8487 | 1 | -1 | 0.3 | 22.05 | 235.6 | 3.8 | 0.1 | 1.2 | 0.1 | 0.1 | X | X | Potentially Pathogenic | The carboxylate group of Asp287, located at the beginning of a β hairpin loop connecting two anti-parallel β sheet strands (res. Arg279-Leu286, res. Met289-Pro298), maintains a salt bridge with the guanidinium group of Arg324 in the β sheet during the WT simulations. In the variant simulations, the imidazole ring of the His287 side chain is unable to form a salt bridge with Arg324 or establish any other stable compensatory interactions, which could weaken the beta sandwich assembly of the C2 domain. This destabilization of the C2 domain could adversely affect the stability of the SynGAP-membrane association. | |||||||||||||||
| c.859G>T | D287Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D287Y missense variant is reported in ClinVar as Pathogenic (ClinVar ID 2263930.0) and is not found in gnomAD. Functional prediction tools show a split: benign calls come from FoldX, Rosetta, Foldetta, and premPS, whereas pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized, a Likely Pathogenic consensus from SGM, and a benign outcome from Foldetta. Overall, the majority of evidence points to a deleterious effect. Therefore, the variant is most likely pathogenic, in agreement with its 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 | Likely Pathogenic | 1 | -12.877 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.21 | Likely Benign | 0.2 | 0.48 | Likely Benign | 0.35 | Likely Benign | 0.27 | Likely Benign | 0.663 | Likely Pathogenic | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 3.38 | 23 | 0.0597 | 0.7361 | -4 | -3 | 2.2 | 48.09 | 257.8 | -44.4 | -0.6 | 1.6 | 0.2 | 0.3 | X | X | Potentially Pathogenic | The carboxylate group of Asp287, located at the beginning of a β hairpin loop linking two anti-parallel β sheet strands (res. Arg279-Leu286, res. Met289-Pro298), maintains a salt bridge with the guanidinium group of Arg324 in the β sheet during the WT simulations. In the variant simulations, the phenol group of the Tyr287 side chain is unable to form a salt bridge with the guanidinium group of Arg324, which could weaken the tertiary structure assembly of the C2 domain. However, the phenol group of Tyr287 frequently stacks with the Arg324 guanidinium side chain, which could help maintain the tertiary structure, especially compared to the D287H variant. The destabilization of the C2 domain could adversely affect the stability of the SynGAP-membrane association. | |||||||||||||||
| c.85A>C | M29L 2D  AIThe SynGAP1 missense variant M29L 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 | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -1.633 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.200 | Likely Benign | -0.49 | Neutral | 0.006 | Benign | 0.039 | Benign | 4.27 | Benign | 0.00 | Affected | 0.1984 | 0.5336 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.85A>G | M29V 2D  AIThe SynGAP1 missense variant M29V is reported in gnomAD (ID 6‑33423494‑A‑G) but has no ClinVar entry. 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. Only SIFT predicts it to be pathogenic, representing the sole discordant signal. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. 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 points to a benign impact for M29V, 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 | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | 6-33423494-A-G | 1 | 6.20e-7 | -1.841 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -0.39 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.27 | Benign | 0.00 | Affected | 4.32 | 1 | 0.4022 | 0.4433 | 1 | 2 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||
| c.85A>T | M29L 2D AIThe SynGAP1 missense variant M29L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect; there is no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -1.633 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.200 | Likely Benign | -0.49 | Neutral | 0.006 | Benign | 0.039 | Benign | 4.27 | Benign | 0.00 | Affected | 0.1984 | 0.5336 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| 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.86T>A | M29K 2D  AIThe SynGAP1 missense variant M29K is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency or clinical annotation. Prediction tools that converge on a benign outcome include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic effect. 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 likewise indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the collective predictions point to a benign effect, and this conclusion does not contradict the absence of a ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -2.514 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.197 | Likely Benign | -0.88 | Neutral | 0.018 | Benign | 0.184 | Benign | 4.27 | Benign | 0.00 | Affected | 0.2019 | 0.1312 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||||||||||||
| c.86T>C | M29T 2D  AIThe SynGAP1 missense variant M29T is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. 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 classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that M29T is most likely benign, and this conclusion does not contradict the current ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | Uncertain | 1 | -2.167 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -0.37 | Neutral | 0.018 | Benign | 0.184 | Benign | 4.33 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2633 | 0.2716 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||
| c.86T>G | M29R 2D  AIThe SynGAP1 missense variant M29R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -1.708 | Likely Benign | 0.241 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -0.92 | Neutral | 0.042 | Benign | 0.184 | Benign | 4.23 | Benign | 0.00 | Affected | 0.2076 | 0.1293 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||||||||||||
| c.877C>T | R293C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R293C is listed in ClinVar with an uncertain significance (ClinVar ID 2500611.0) and is present in gnomAD (6‑33437782‑C‑T). Prediction tools that classify the variant as benign include premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Consequently, the overwhelming majority of computational evidence indicates a pathogenic impact for R293C. This prediction aligns with the ClinVar designation of uncertain significance, not contradicting it. 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 | 6-33437782-C-T | 3 | 1.86e-6 | -12.844 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.38 | Ambiguous | 0.1 | 0.62 | Ambiguous | 1.00 | Ambiguous | 0.02 | Likely Benign | 0.579 | Likely Pathogenic | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.46 | Pathogenic | 0.00 | Affected | 3.38 | 23 | 0.3031 | 0.4363 | -4 | -3 | 7.0 | -53.05 | 226.0 | 96.5 | 0.0 | 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. The positively charged guanidinium side chain of arginine is on the outside surface of the hydrophobic C2 domain, resulting in a twist in the β strand. Although this twist is maintained in the variant simulations, replacing the positively charged residue with a more hydrophobic one, such as cysteine, could remove the twist during protein folding.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.87G>A | M29I 2D  AIThe SynGAP1 missense variant M29I is catalogued in gnomAD (6-33423496‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while the single pathogenic signal comes from SIFT. 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 predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. Foldetta stability analysis is unavailable for this variant. Overall, the preponderance of evidence points to a benign 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 Benign | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | 6-33423496-G-A | 6 | 3.72e-6 | -2.425 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.51 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.26 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1680 | 0.4385 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||
| c.87G>C | M29I 2D AIThe SynGAP1 missense variant M29I 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 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 | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -2.425 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.51 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.26 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1680 | 0.4385 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.87G>T | M29I 2D AIThe SynGAP1 missense variant M29I 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. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438540 | Uncertain | 0.341 | 0.883 | 0.250 | -2.425 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.51 | Neutral | 0.006 | Benign | 0.091 | Benign | 4.26 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1680 | 0.4385 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||||
| c.88C>A | H30N 2D AIThe SynGAP1 missense variant H30N is not reported in ClinVar and is absent from gnomAD. Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, while only SIFT predicts pathogenicity. Grouping the tools, the benign‑predicting set (nine tools) overwhelmingly outweighs the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | -3.096 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -1.91 | Neutral | 0.273 | Benign | 0.380 | Benign | 3.92 | Benign | 0.00 | Affected | 0.2699 | 0.3818 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.88C>G | H30D 2D AIThe SynGAP1 missense variant H30D 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‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: 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 H30D, 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 | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | -2.838 | Likely Benign | 0.318 | Likely Benign | Likely Benign | 0.150 | Likely Benign | -2.25 | Neutral | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.3048 | 0.3296 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||||||||||||
| c.88C>T | H30Y 2D AIThe SynGAP1 H30Y missense variant (ClinVar ID 972248.0) is listed as “Uncertain” and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, 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 HumVar and SIFT. 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 effect, 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 | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | Uncertain | 1 | -3.047 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -1.84 | Neutral | 0.273 | Benign | 0.478 | Possibly Damaging | 3.99 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1572 | 0.4856 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||||||
| c.890A>T | K297M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297M is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, and premPS. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as Pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports Likely Pathogenic; whereas Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, reports a Benign effect. Overall, the preponderance of evidence (10 pathogenic vs. 4 benign predictions) points to the variant being most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -11.472 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.09 | Likely Benign | 0.1 | 0.32 | Likely Benign | 0.21 | Likely Benign | 0.49 | Likely Benign | 0.538 | Likely Pathogenic | -5.20 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.61 | Pathogenic | 0.00 | Affected | 0.1438 | 0.4394 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.89A>C | H30P 2D AIThe SynGAP1 H30P missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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 effect, 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 | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | -1.933 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.202 | Likely Benign | -2.77 | Deleterious | 0.676 | Possibly Damaging | 0.599 | Possibly Damaging | 3.89 | Benign | 0.00 | Affected | 0.2527 | 0.4723 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.89A>G | H30R 2D AIThe SynGAP1 missense variant H30R 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‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are 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 conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | -2.156 | Likely Benign | 0.186 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -2.17 | Neutral | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.94 | Benign | 0.00 | Affected | 0.2762 | 0.3590 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.89A>T | H30L 2D AIThe SynGAP1 H30L 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, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (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 (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a 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 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 | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | -2.073 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.163 | Likely Benign | -2.88 | Deleterious | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.94 | Benign | 0.00 | Affected | 0.1523 | 0.5793 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||||||||||||
| c.8G>A | R3K 2D AIThe SynGAP1 missense variant R3K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction 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 Benign | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -4.378 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.45 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.09 | Benign | 0.00 | Affected | 0.5842 | 0.4564 | Weaken | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||||||
| c.8G>C | R3T 2D AIThe SynGAP1 missense variant R3T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -3.693 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.55 | Neutral | 0.208 | Benign | 0.018 | Benign | 4.01 | Benign | 0.00 | Affected | 0.1809 | 0.5145 | -1 | -1 | 3.8 | -55.08 | |||||||||||||||||||||||||||||||||||||||
| c.8G>T | R3M 2D  AIThe SynGAP1 missense variant R3M 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, SIFT, and AlphaMissense‑Default. The high‑accuracy consensus methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” and Foldetta data are unavailable. Overall, the majority of evidence supports a benign classification, 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 Benign | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -4.655 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | 0.00 | Neutral | 0.872 | Possibly Damaging | 0.162 | Benign | 3.96 | Benign | 0.00 | Affected | 0.1906 | 0.4795 | 0 | -1 | 6.4 | -24.99 | |||||||||||||||||||||||||||||||||||||||
| c.907G>T | G303W 2D  3DClick to see structure in 3D Viewer AIClinVar reports no entry for this SynGAP1 G303W variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta’s stability prediction is also unavailable. Overall, the evidence is evenly split between benign and pathogenic predictions, providing no clear bias toward either outcome. This balanced prediction does not contradict ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -9.041 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 1.69 | Ambiguous | 0.3 | 1.11 | Ambiguous | 1.40 | Ambiguous | 0.28 | Likely Benign | 0.157 | Likely Benign | -1.63 | Neutral | 0.983 | Probably Damaging | 0.813 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 0.0663 | 0.4553 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||||
| c.90C>A | H30Q 2D AIThe SynGAP1 H30Q missense change is catalogued in gnomAD (ID 6‑33423499‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: six methods (REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score all indicate a benign effect, while three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (derived from the four benign‑predicting tools) also yields a benign verdict. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with ClinVar, which currently contains no classification for H30Q. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | 6-33423499-C-A | 1 | 6.20e-7 | -3.016 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -2.21 | Neutral | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2409 | 0.4422 | 0 | 3 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||
| c.90C>G | H30Q 2D AIThe SynGAP1 missense variant H30Q 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. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. 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 majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.570702 | Disordered | 0.438063 | Uncertain | 0.373 | 0.883 | 0.250 | -3.016 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -2.21 | Neutral | 0.462 | Possibly Damaging | 0.599 | Possibly Damaging | 3.93 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2409 | 0.4422 | 0 | 3 | -0.3 | -9.01 | |||||||||||||||||||||||||||||||||||||
| c.910G>T | D304Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304Y missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, Foldetta, and premPS, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also labeled Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. With the majority of evidence pointing toward pathogenicity, the variant is most likely pathogenic; this assessment does not conflict with ClinVar, which contains no entry for D304Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -10.495 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.60 | Ambiguous | 0.2 | 0.14 | Likely Benign | 0.37 | Likely Benign | 0.37 | Likely Benign | 0.468 | Likely Benign | -6.29 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.76 | Pathogenic | 0.00 | Affected | 0.0623 | 0.6566 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.911A>T | D304V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304V missense variant is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include Rosetta and premPS, while the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D304V. This conclusion is not contradicted by ClinVar, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -8.280 | Likely Pathogenic | 0.803 | Likely Pathogenic | Ambiguous | 1.35 | Ambiguous | 0.3 | 0.14 | Likely Benign | 0.75 | Ambiguous | 0.35 | Likely Benign | 0.541 | Likely Pathogenic | -6.22 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.81 | Pathogenic | 0.00 | Affected | 0.0971 | 0.6999 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.917T>A | V306D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. All available in‑silico predictors that were evaluated return a pathogenic or likely‑pathogenic assessment: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the unanimous pathogenic predictions, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | Uncertain | 1 | -18.289 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 4.40 | Destabilizing | 0.3 | 4.29 | Destabilizing | 4.35 | Destabilizing | 2.44 | Destabilizing | 0.530 | Likely Pathogenic | -5.44 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.74 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.1317 | 0.0768 | -2 | -3 | -7.7 | 15.96 | 212.3 | -18.3 | -0.2 | 0.4 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The isopropyl group of Val396, located at the beginning of an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Leu274, Trp308, Ala271) in the WT simulations. However, in the variant simulations, the negatively charged carboxylate group of the Asp306 side chain is not suitable for this hydrophobic niche. Consequently, the side chain moves out to interact with Ser300 in the β strand (res. Met289-Arg299) and the guanidinium group of Arg299 in the β hairpin loop.In the third simulation, the residue swap disrupts the C2 domain secondary structure and tertiary assembly to a large degree when the amino group of the Lys297 side chain rotates to form a salt bridge with Asp306. This drastic effect could potentially reflect the challenge presented by the residue swap during the C2 domain folding. Because the residue swap affects the C2 domain structure, the SynGAP-membrane association could also be impacted. However, this is beyond the scope of the solvent-only simulations to unravel. | ||||||||||||||
| c.917T>G | V306G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: 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 pathogenic. All available evidence points to a pathogenic effect. Therefore, 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. | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | -12.313 | Likely Pathogenic | 0.795 | Likely Pathogenic | Ambiguous | 4.39 | Destabilizing | 0.2 | 5.89 | Destabilizing | 5.14 | Destabilizing | 2.46 | Destabilizing | 0.529 | Likely Pathogenic | -5.48 | Deleterious | 0.998 | Probably Damaging | 1.000 | Probably Damaging | 1.78 | Pathogenic | 0.00 | Affected | 0.1874 | 0.2035 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.91C>G | R31G 2D AIThe SynGAP1 missense variant R31G 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 returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for R31G, 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 | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.259 | Likely Benign | 0.269 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -1.77 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 3.97 | Benign | 0.00 | Affected | 0.3389 | 0.3942 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.920T>G | F307C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 F307C missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). In silico predictors overwhelmingly indicate a deleterious effect: all tools that provide a definitive call—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. The only predictions that are inconclusive are FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. **Based on the consensus of the available predictions, the variant is most likely pathogenic, and this assessment is not contradicted by any ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.298791 | Structured | 0.327302 | Uncertain | 0.900 | 0.315 | 0.125 | -11.484 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.36 | Ambiguous | 0.1 | 1.44 | Ambiguous | 1.40 | Ambiguous | 1.05 | Destabilizing | 0.754 | Likely Pathogenic | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.92 | Pathogenic | 0.00 | Affected | 0.2729 | 0.1628 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.922T>A | W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the consensus of all available predictions, the variant is most likely pathogenic, 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 | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -12.264 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.40 | Destabilizing | 0.5 | 4.27 | Destabilizing | 4.84 | Destabilizing | 1.88 | Destabilizing | 0.868 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.4751 | 0.0361 | 2 | -3 | -3.6 | -30.03 | 290.4 | -26.7 | -0.1 | 0.1 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||||
| c.922T>C | W308R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308R is listed in ClinVar (ID 391294.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the change as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | Pathogenic | 1 | -12.264 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.40 | Destabilizing | 0.5 | 4.27 | Destabilizing | 4.84 | Destabilizing | 1.88 | Destabilizing | 0.868 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.4751 | 0.0361 | 2 | -3 | -3.6 | -30.03 | 290.4 | -26.7 | -0.1 | 0.1 | 0.0 | 0.2 | X | X | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The guanidinium group of Arg308 is comparably sized to the tryptophan it replaced; however, it is also positively charged.In the variant simulations, the charged side chain remains buried deep in the hydrophobic part of the C2 domain, where it forms new hydrogen bonds with the backbone carbonyl atoms of surrounding residues (e.g., Val306, Ile268). However, the residue swap is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||
| c.922T>G | W308G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308G is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this view: 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 unanimous predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -16.271 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.88 | Destabilizing | 0.2 | 5.07 | Destabilizing | 5.98 | Destabilizing | 1.97 | Destabilizing | 0.860 | Likely Pathogenic | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 0.4884 | 0.1644 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||
| c.923G>C | W308S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308S is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -15.425 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.42 | Destabilizing | 0.2 | 5.31 | Destabilizing | 5.87 | Destabilizing | 1.93 | Destabilizing | 0.861 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 0.5089 | 0.1406 | Weaken | -2 | -3 | 0.1 | -99.14 | ||||||||||||||||||||||||||||
| c.923G>T | W308L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates “Likely Pathogenic.” Only Rosetta and premPS yield uncertain results, which are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No tools predict benign effects. **Based on the collective 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 | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -13.349 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 3.53 | Destabilizing | 0.5 | 1.52 | Ambiguous | 2.53 | Destabilizing | 0.53 | Ambiguous | 0.811 | Likely Pathogenic | -11.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 0.49 | Pathogenic | 0.00 | Affected | 0.2731 | 0.2754 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||
| c.924G>C | W308C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is listed in ClinVar as Pathogenic (ClinVar ID 981381.0) and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Pathogenic”; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | Pathogenic/Likely path. | 2 | -12.791 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.56 | Destabilizing | 0.3 | 4.38 | Destabilizing | 4.97 | Destabilizing | 1.26 | Destabilizing | 0.738 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.4390 | 0.1621 | -8 | -2 | 3.4 | -83.07 | 230.8 | 60.5 | -0.3 | 0.1 | -0.4 | 0.4 | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||||
| c.924G>T | W308C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W308C is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a deleterious effect. Therefore, 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 | 0.328603 | Structured | 0.333942 | Uncertain | 0.907 | 0.314 | 0.125 | -12.791 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.56 | Destabilizing | 0.3 | 4.38 | Destabilizing | 4.97 | Destabilizing | 1.26 | Destabilizing | 0.738 | Likely Pathogenic | -11.95 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.48 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.4390 | 0.1621 | -8 | -2 | 3.4 | -83.07 | 230.8 | 60.5 | -0.3 | 0.1 | -0.4 | 0.4 | X | Potentially Pathogenic | The indole ring of Trp308, located in an anti-parallel β sheet strand (res. Thr305-Asn315), packs against multiple hydrophobic residues (e.g., Ile268, Val306, Cys282). The indole group of Trp308 also hydrogen bonds with the backbone atoms of the C2 domain residues forming the anti-parallel β sheet (e.g., Tyr280, Thr294). The introduced Cys308 is smaller than the tryptophan it replaced. The thiol group of the Cys308 side chain is well-suited for the inner hydrophobic part of the C2 domain. Although the negative effects are essentially missing from the simulations, the side chain size difference between the residues is likely to disrupt the hydrophobic packing during folding. At a minimum, the residue swap could affect the C2 domain stability and membrane association. | ||||||||||||||||||
| c.925G>T | G309C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a deleterious effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score, all of which classify the change as pathogenic or likely pathogenic. Tools with inconclusive results—Rosetta, Foldetta, and premPS—return uncertain outcomes and do not alter the overall assessment. High‑accuracy methods further support a damaging effect: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, whereas Foldetta’s stability analysis is inconclusive. Taken together, the evidence strongly favors a pathogenic interpretation, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -14.331 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.60 | Destabilizing | 0.4 | 1.09 | Ambiguous | 1.85 | Ambiguous | 0.67 | Ambiguous | 0.656 | Likely Pathogenic | -8.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.66 | Pathogenic | 0.00 | Affected | 0.1378 | 0.4574 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.926G>T | G309V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309V is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -13.595 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.55 | Destabilizing | 0.5 | 3.61 | Destabilizing | 4.08 | Destabilizing | 0.76 | Ambiguous | 0.531 | Likely Pathogenic | -8.27 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.67 | Pathogenic | 0.00 | Affected | 0.1256 | 0.3910 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.929A>G | E310G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E310G is listed in ClinVar as Pathogenic (ClinVar ID 2732842.0) and is not reported in gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only premPS predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this prediction is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | Pathogenic | 1 | -14.132 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.38 | Destabilizing | 0.7 | 3.56 | Destabilizing | 2.97 | Destabilizing | 0.36 | Likely Benign | 0.848 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.12 | Pathogenic | 0.00 | Affected | 3.38 | 19 | 0.2736 | 0.6932 | -2 | 0 | 3.1 | -72.06 | |||||||||||||||||||||||||
| c.929A>T | E310V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E310V missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are Rosetta and premPS, while the majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that E310V 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 | C2 | 0.222385 | Structured | 0.346136 | Uncertain | 0.914 | 0.337 | 0.125 | -15.494 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.08 | Ambiguous | 0.9 | 0.06 | Likely Benign | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.871 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.12 | Pathogenic | 0.00 | Affected | 0.0849 | 0.8729 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.92G>A | R31Q 2D AIThe SynGAP1 missense variant R31Q is listed in ClinVar (ID 1977609.0) with an “Uncertain” status and is present in gnomAD (6‑33423501‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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, which does not contradict the ClinVar “Uncertain” classification and suggests the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | Uncertain | 1 | 6-33423501-G-A | 7 | 4.34e-6 | -4.434 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.92 | Neutral | 0.829 | Possibly Damaging | 0.614 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3605 | 0.3355 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||||||||||
| c.92G>C | R31P 2D AIThe SynGAP1 missense variant R31P 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. 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 predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of computational evidence points to a benign impact for R31P, 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 | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.185 | Likely Benign | 0.300 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -1.64 | Neutral | 0.841 | Possibly Damaging | 0.809 | Possibly Damaging | 3.96 | Benign | 0.00 | Affected | 0.2220 | 0.5005 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||||||
| c.92G>T | R31L 2D AIThe SynGAP1 missense variant R31L is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict pathogenic. AlphaMissense‑Default remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically indicate benign: AlphaMissense‑Optimized is benign, SGM‑Consensus is Likely Benign, and Foldetta data are missing. Overall, the majority of reliable predictions lean toward a benign effect, 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 | 0.549308 | Disordered | 0.437905 | Uncertain | 0.324 | 0.878 | 0.250 | -3.147 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -1.79 | Neutral | 0.686 | Possibly Damaging | 0.630 | Possibly Damaging | 4.01 | Benign | 0.00 | Affected | 0.2264 | 0.5148 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.934T>G | F312V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312V is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the change as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous 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 | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -12.206 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.13 | Destabilizing | 0.1 | 3.46 | Destabilizing | 2.80 | Destabilizing | 1.80 | Destabilizing | 0.877 | Likely Pathogenic | -6.43 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.25 | Pathogenic | 0.00 | Affected | 0.1998 | 0.2810 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.935T>C | F312S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All available in‑silico predictors classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, with no contradiction to ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -14.075 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 3.74 | Destabilizing | 0.3 | 5.64 | Destabilizing | 4.69 | Destabilizing | 2.70 | Destabilizing | 0.880 | Likely Pathogenic | -7.35 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.17 | Pathogenic | 0.00 | Affected | 0.3563 | 0.1578 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.935T>G | F312C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F312C is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity uniformly classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic impact. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.225814 | Structured | 0.361163 | Uncertain | 0.915 | 0.317 | 0.000 | -11.991 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.98 | Destabilizing | 0.3 | 4.97 | Destabilizing | 3.98 | Destabilizing | 1.46 | Destabilizing | 0.870 | Likely Pathogenic | -7.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.16 | Pathogenic | 0.00 | Affected | 0.2293 | 0.2010 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.940T>G | F314V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). All available in silico predictors classify the variant as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta—each return a pathogenic prediction. No predictions or stability results are missing or inconclusive. Based on the unanimous 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 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -8.907 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 3.31 | Destabilizing | 0.4 | 2.54 | Destabilizing | 2.93 | Destabilizing | 1.44 | Destabilizing | 0.594 | Likely Pathogenic | -5.90 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.26 | Pathogenic | 0.00 | Affected | 0.2054 | 0.2075 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.941T>C | F314S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314S (located in the C2 domain) is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this: 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) predicts a destabilizing, pathogenic effect. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -14.371 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 4.51 | Destabilizing | 0.4 | 3.36 | Destabilizing | 3.94 | Destabilizing | 2.59 | Destabilizing | 0.735 | Likely Pathogenic | -6.95 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.15 | Pathogenic | 0.00 | Affected | 0.4113 | 0.0600 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.941T>G | F314C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F314C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. All available evidence points to a damaging effect. Consequently, 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 | C2 | 0.173081 | Structured | 0.374049 | Uncertain | 0.900 | 0.271 | 0.125 | -12.458 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.37 | Destabilizing | 0.3 | 2.64 | Destabilizing | 3.01 | Destabilizing | 2.49 | Destabilizing | 0.674 | Likely Pathogenic | -6.89 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.13 | Pathogenic | 0.00 | Affected | 0.2401 | 0.1075 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.94A>C | T32P 2D  AIThe SynGAP1 missense variant T32P 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. In contrast, two tools—polyPhen‑2 HumDiv and SIFT—classify the change as pathogenic. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | -2.958 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.102 | Likely Benign | -0.94 | Neutral | 0.604 | Possibly Damaging | 0.185 | Benign | 4.14 | Benign | 0.00 | Affected | 0.2327 | 0.5818 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||||||||||||
| c.94A>G | T32A 2D  AIThe SynGAP1 missense variant T32A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | -3.330 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.63 | Neutral | 0.043 | Benign | 0.016 | Benign | 4.21 | Benign | 0.00 | Affected | 0.4174 | 0.4742 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.94A>T | T32S 2D  AIThe SynGAP1 missense variant T32S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | -2.618 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.39 | Neutral | 0.171 | Benign | 0.050 | Benign | 4.18 | Benign | 0.00 | Affected | 0.3603 | 0.5174 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.950T>A | L317Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on 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 | 0.106997 | Structured | 0.394031 | Uncertain | 0.874 | 0.240 | 0.125 | -13.424 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.87 | Destabilizing | 0.2 | 2.47 | Destabilizing | 2.67 | Destabilizing | 1.61 | Destabilizing | 0.607 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.00 | Affected | 0.1252 | 0.1251 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.950T>C | L317P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tools predict a benign effect, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.106997 | Structured | 0.394031 | Uncertain | 0.874 | 0.240 | 0.125 | -14.778 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.61 | Destabilizing | 1.4 | 4.29 | Destabilizing | 3.95 | Destabilizing | 1.26 | Destabilizing | 0.654 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.82 | Pathogenic | 0.00 | Affected | 0.3405 | 0.1153 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.950T>G | L317R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L317R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.106997 | Structured | 0.394031 | Uncertain | 0.874 | 0.240 | 0.125 | -14.185 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.33 | Destabilizing | 0.2 | 2.01 | Destabilizing | 2.67 | Destabilizing | 1.63 | Destabilizing | 0.569 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.75 | Pathogenic | 0.00 | Affected | 0.1501 | 0.0893 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.95C>A | T32N 2D  AIThe SynGAP1 missense variant T32N is catalogued in gnomAD (ID 6‑33423504‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: 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 reported result for this variant, so its status is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | 6-33423504-C-A | 2 | 1.24e-6 | -3.466 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -1.01 | Neutral | 0.604 | Possibly Damaging | 0.140 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1681 | 0.5264 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||||
| c.95C>G | T32S 2D AIThe SynGAP1 missense variant T32S is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | -2.618 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.39 | Neutral | 0.171 | Benign | 0.050 | Benign | 4.18 | Benign | 0.00 | Affected | 0.3603 | 0.5174 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.95C>T | T32I 2D  AIThe SynGAP1 missense variant T32I is reported in gnomAD (ID 6‑33423504‑C‑T) but has no ClinVar entry. 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. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for T32I, 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 | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | 6-33423504-C-T | 1 | 6.20e-7 | -3.689 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.57 | Neutral | 0.049 | Benign | 0.026 | Benign | 4.26 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1081 | 0.6403 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||
| c.968T>A | L323Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L323Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.268042 | Structured | 0.428564 | Uncertain | 0.956 | 0.369 | 0.000 | -14.487 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 3.19 | Destabilizing | 0.2 | 3.28 | Destabilizing | 3.24 | Destabilizing | 1.85 | Destabilizing | 0.728 | Likely Pathogenic | -4.54 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 0.59 | Pathogenic | 0.00 | Affected | 0.0915 | 0.0758 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.974T>A | L325Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify it as pathogenic. Benign predictions are absent; all evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—return pathogenic or likely pathogenic calls. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. Consequently, the variant is most likely pathogenic, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -17.005 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.23 | Destabilizing | 0.0 | 2.68 | Destabilizing | 2.96 | Destabilizing | 2.02 | Destabilizing | 0.547 | Likely Pathogenic | -3.97 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 1.33 | Pathogenic | 0.00 | Affected | 0.1235 | 0.1405 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.974T>C | L325P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325P is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -16.130 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.49 | Destabilizing | 0.3 | 7.27 | Destabilizing | 6.38 | Destabilizing | 1.89 | Destabilizing | 0.607 | Likely Pathogenic | -4.37 | Deleterious | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 1.33 | Pathogenic | 0.00 | Affected | 0.3393 | 0.1903 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.974T>G | L325R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L325R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (no ClinVar entry).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -16.612 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.34 | Destabilizing | 0.3 | 4.11 | Destabilizing | 4.23 | Destabilizing | 1.94 | Destabilizing | 0.551 | Likely Pathogenic | -4.39 | Deleterious | 0.999 | Probably Damaging | 0.969 | Probably Damaging | 1.33 | Pathogenic | 0.00 | Affected | 0.1405 | 0.1047 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.97C>A | Q33K 2D  AIThe SynGAP1 missense variant Q33K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. 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 Benign | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | -0.317 | Likely Benign | 0.217 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.53 | Neutral | 0.019 | Benign | 0.021 | Benign | 4.24 | Benign | 0.00 | Affected | 0.2366 | 0.4514 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.97C>G | Q33E 2D  AIThe SynGAP1 missense variant Q33E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. 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 further support a benign status: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | 0.191 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.13 | Neutral | 0.017 | Benign | 0.014 | Benign | 4.25 | Benign | 0.00 | Affected | 0.1773 | 0.3326 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.980T>A | L327Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. With all available evidence pointing to a harmful impact and no ClinVar entry to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.409189 | Uncertain | 0.939 | 0.490 | 0.000 | -14.243 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 0.1 | 2.17 | Destabilizing | 2.60 | Destabilizing | 2.11 | Destabilizing | 0.605 | Likely Pathogenic | -5.26 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.52 | Pathogenic | 0.00 | Affected | 0.1131 | 0.1042 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.980T>G | L327R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. All available predictions are concordant and indicate a likely pathogenic impact. Thus, based on the current computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.409189 | Uncertain | 0.939 | 0.490 | 0.000 | -13.403 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.46 | Destabilizing | 0.3 | 4.75 | Destabilizing | 4.61 | Destabilizing | 1.95 | Destabilizing | 0.619 | Likely Pathogenic | -5.28 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.52 | Pathogenic | 0.00 | Affected | 0.1281 | 0.1085 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.985C>T | R329C 2D 3DClick to see structure in 3D Viewer AISynGAP1 R329C is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33437890‑C‑T). Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, and FATHMM; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: 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 (integrating FoldX‑MD and Rosetta) as benign. Overall, the majority of conventional predictors lean toward pathogenicity, whereas the high‑accuracy Foldetta result is benign, leaving the variant’s effect ambiguous. Based on the prevailing predictions, the variant is most likely pathogenic, which contrasts with its ClinVar uncertain designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.376086 | Uncertain | 0.887 | 0.479 | 0.250 | Uncertain | 1 | 6-33437890-C-T | 2 | 1.24e-6 | -9.433 | Likely Pathogenic | 0.865 | Likely Pathogenic | Ambiguous | 0.44 | Likely Benign | 0.1 | 0.40 | Likely Benign | 0.42 | Likely Benign | 0.69 | Ambiguous | 0.313 | Likely Benign | -5.70 | Deleterious | 0.999 | Probably Damaging | 0.825 | Possibly Damaging | 3.98 | Benign | 0.00 | Affected | 3.41 | 15 | 0.3553 | 0.2921 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| 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.98A>C | Q33P 2D  AIThe SynGAP1 missense variant Q33P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | 0.546 | Likely Benign | 0.049 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -0.75 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.21 | Benign | 0.00 | Affected | 0.2445 | 0.5623 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||||||||||||
| c.98A>G | Q33R 2D  AIThe SynGAP1 missense variant Q33R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The predictions do not contradict ClinVar status, as ClinVar contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | 0.561 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -0.82 | Neutral | 0.084 | Benign | 0.046 | Benign | 4.20 | Benign | 0.00 | Affected | 0.1936 | 0.2773 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.98A>T | Q33L 2D  AIThe SynGAP1 missense variant Q33L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. 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 further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | 0.253 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -1.24 | Neutral | 0.084 | Benign | 0.033 | Benign | 4.18 | Benign | 0.00 | Affected | 0.1127 | 0.6214 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| 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.99A>C | Q33H 2D  AIThe SynGAP1 missense variant Q33H 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the variant, 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 | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | -0.450 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.95 | Neutral | 0.704 | Possibly Damaging | 0.198 | Benign | 4.16 | Benign | 0.00 | Affected | 0.1856 | 0.4509 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.99A>T | Q33H 2D AIThe SynGAP1 missense variant Q33H 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the variant, 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 | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | -0.450 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.95 | Neutral | 0.704 | Possibly Damaging | 0.198 | Benign | 4.16 | Benign | 0.00 | Affected | 0.1856 | 0.4509 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.9G>C | R3S 2D AIThe SynGAP1 missense variant R3S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect. The prediction 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 Benign | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | -2.296 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -0.53 | Neutral | 0.115 | Benign | 0.013 | Benign | 4.02 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3148 | 0.4732 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||
| c.9G>T | R3S 2D AIThe SynGAP1 missense variant R3S is reported in gnomAD (ID 6‑33420273‑G‑T) but has no ClinVar entry. 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. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign effect. 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 | 0.538167 | Disordered | 0.550331 | Binding | 0.358 | 0.920 | 0.875 | 6-33420273-G-T | 1 | 6.50e-7 | -2.296 | Likely Benign | 0.310 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -0.53 | Neutral | 0.115 | Benign | 0.013 | Benign | 4.02 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3148 | 0.4732 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||
| c.1001A>T | K334M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K334M 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, FoldX, and premPS. In contrast, the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as Likely Pathogenic. Foldetta and Rosetta provide uncertain results. Focusing on high‑accuracy methods, AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus confirms a Likely Pathogenic status, and Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K334M, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.377384 | Structured | 0.325972 | Uncertain | 0.544 | 0.414 | 0.500 | -10.530 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.44 | Likely Benign | 0.0 | 0.56 | Ambiguous | 0.50 | Ambiguous | 0.14 | Likely Benign | 0.323 | Likely Benign | -5.51 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.77 | Pathogenic | 0.01 | Affected | 0.1027 | 0.3690 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1003C>T | R335C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R335C is listed in ClinVar with an uncertain significance (ClinVar ID 2835865.0) and is present in gnomAD (ID 6‑33437908‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are AlphaMissense‑Optimized, FoldX, Rosetta, and Foldetta. 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 as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion aligns with the ClinVar designation of uncertain significance, which does not contradict the prediction that the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.305330 | Structured | 0.331028 | Uncertain | 0.483 | 0.428 | 0.500 | Uncertain | 1 | 6-33437908-C-T | 1 | 6.20e-7 | -14.354 | Likely Pathogenic | 0.938 | Likely Pathogenic | Ambiguous | 0.53 | Ambiguous | 0.1 | 0.85 | Ambiguous | 0.69 | Ambiguous | 0.46 | Likely Benign | 0.277 | Likely Benign | -5.69 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.67 | Pathogenic | 0.01 | Affected | 3.38 | 22 | 0.2882 | 0.3290 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| c.1006A>G | K336E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336E 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, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 toward a pathogenic impact for K336E, 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 | 0.318242 | Structured | 0.338219 | Uncertain | 0.396 | 0.428 | 0.500 | -16.091 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | -0.28 | Likely Benign | 0.0 | 0.19 | Likely Benign | -0.05 | Likely Benign | 0.35 | Likely Benign | 0.236 | Likely Benign | -3.43 | Deleterious | 0.625 | Possibly Damaging | 0.192 | Benign | 1.60 | Pathogenic | 0.01 | Affected | 0.4003 | 0.1082 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1007A>C | K336T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336T 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 polyPhen‑2 HumVar. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy assessment shows 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 toward a pathogenic impact for K336T, 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 | 0.318242 | Structured | 0.338219 | Uncertain | 0.396 | 0.428 | 0.500 | -13.468 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.33 | Likely Benign | 0.1 | -0.08 | Likely Benign | 0.13 | Likely Benign | 0.15 | Likely Benign | 0.212 | Likely Benign | -4.94 | Deleterious | 0.891 | Possibly Damaging | 0.315 | Benign | 1.58 | Pathogenic | 0.01 | Affected | 0.2014 | 0.4048 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1008G>C | K336N 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant K336N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome. High‑accuracy assessments further highlight this split: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus also predicts likely pathogenic, while Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. No prediction or stability result is missing. Overall, the majority of tools and the high‑accuracy methods lean toward pathogenicity, 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.318242 | Structured | 0.338219 | Uncertain | 0.396 | 0.428 | 0.500 | -13.307 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.09 | Likely Benign | 0.20 | Likely Benign | 0.186 | Likely Benign | -4.09 | Deleterious | 0.801 | Possibly Damaging | 0.315 | Benign | 1.59 | Pathogenic | 0.01 | Affected | 0.3710 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1008G>T | K336N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K336N is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and polyPhen‑2 HumVar. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, 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 majority of evidence points toward a pathogenic impact for K336N, 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 | 0.318242 | Structured | 0.338219 | Uncertain | 0.396 | 0.428 | 0.500 | -13.307 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.20 | Likely Benign | 0.1 | -0.02 | Likely Benign | 0.09 | Likely Benign | 0.20 | Likely Benign | 0.186 | Likely Benign | -4.09 | Deleterious | 0.801 | Possibly Damaging | 0.315 | Benign | 1.59 | Pathogenic | 0.01 | Affected | 0.3710 | 0.1599 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1009A>C | K337Q 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 K337Q 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 Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), 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 as Likely Pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of predictions (8 pathogenic vs. 4 benign) indicate 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 | 0.321458 | Structured | 0.348540 | Uncertain | 0.449 | 0.438 | 0.500 | -9.944 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.00 | Likely Benign | 0.0 | 0.88 | Ambiguous | 0.44 | Likely Benign | 0.43 | Likely Benign | 0.305 | Likely Benign | -3.48 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 0.3672 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1010A>C | K337T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K337T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, FoldX, and premPS, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Three tools report uncertainty: Rosetta, Foldetta, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic. In the high‑accuracy subset, AlphaMissense‑Optimized remains uncertain, SGM‑Consensus is Likely Pathogenic, and Foldetta is uncertain. Taken together, the majority of evidence points toward a deleterious effect. Therefore, K337T is most likely pathogenic, 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 | 0.321458 | Structured | 0.348540 | Uncertain | 0.449 | 0.438 | 0.500 | -10.896 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.45 | Likely Benign | 0.2 | 1.33 | Ambiguous | 0.89 | Ambiguous | 0.25 | Likely Benign | 0.338 | Likely Benign | -5.32 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 0.1741 | 0.3354 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1012G>C | D338H 2D AIThe SynGAP1 missense variant D338H is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions are limited to premPS, whereas the remaining 11 tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all classify the variant as pathogenic or likely 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, while Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for D338H, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -12.325 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | 1.32 | Ambiguous | 1.2 | 0.76 | Ambiguous | 1.04 | Ambiguous | 0.18 | Likely Benign | 0.515 | Likely Pathogenic | -4.42 | Deleterious | 0.966 | Probably Damaging | 0.770 | Possibly Damaging | 1.71 | Pathogenic | 0.01 | Affected | 0.1671 | 0.6654 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| 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.1013A>T | D338V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D338V missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No prediction or folding‑stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that 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 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -11.494 | Likely Pathogenic | 0.927 | Likely Pathogenic | Ambiguous | 1.64 | Ambiguous | 0.2 | 1.08 | Ambiguous | 1.36 | Ambiguous | 0.23 | Likely Benign | 0.553 | Likely Pathogenic | -6.79 | Deleterious | 0.891 | Possibly Damaging | 0.492 | Possibly Damaging | 1.73 | Pathogenic | 0.01 | Affected | 0.0879 | 0.5745 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.1016A>T | K339M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K339M 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 FoldX and premPS, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for K339M. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.447574 | Structured | 0.384153 | Uncertain | 0.535 | 0.465 | 0.250 | -13.387 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.23 | Likely Benign | 0.0 | 0.88 | Ambiguous | 0.56 | Ambiguous | -0.37 | Likely Benign | 0.575 | Likely Pathogenic | -4.95 | Deleterious | 0.999 | Probably Damaging | 0.964 | Probably Damaging | 1.92 | Pathogenic | 0.01 | Affected | 0.0967 | 0.3541 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| 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.1027G>T | V343F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343F 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, whereas pathogenic predictions are made by SIFT, polyPhen‑2 (HumDiv and HumVar), PROVEAN, 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 are mixed: AlphaMissense‑Optimized is uncertain; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. No evidence from FoldX or Rosetta alone is available. Overall, the majority of predictions support 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 | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -10.709 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 1.51 | Ambiguous | 0.4 | 1.28 | Ambiguous | 1.40 | Ambiguous | 0.23 | Likely Benign | 0.324 | Likely Benign | -3.37 | Deleterious | 0.976 | Probably Damaging | 0.759 | Possibly Damaging | 1.61 | Pathogenic | 0.01 | Affected | 0.0915 | 0.4552 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1028T>C | V343A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343A 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 AlphaMissense‑Optimized, whereas the remaining tools—SGM‑Consensus, FoldX (uncertain), 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 this: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenicity. Overall, the preponderance of evidence points to a pathogenic effect for V343A, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -8.088 | Likely Pathogenic | 0.588 | Likely Pathogenic | Likely Benign | 1.66 | Ambiguous | 0.1 | 2.33 | Destabilizing | 2.00 | Destabilizing | 1.69 | Destabilizing | 0.218 | Likely Benign | -3.15 | Deleterious | 0.826 | Possibly Damaging | 0.551 | Possibly Damaging | 1.63 | Pathogenic | 0.01 | Affected | 0.3137 | 0.3301 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1030G>C | G344R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344R is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while the only inconclusive result is premPS, which is listed as uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic status; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. Consequently, the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -12.609 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.84 | Destabilizing | 0.8 | 13.66 | Destabilizing | 14.25 | Destabilizing | 0.81 | Ambiguous | 0.801 | Likely Pathogenic | -7.17 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.49 | Pathogenic | 0.01 | Affected | 0.0844 | 0.4614 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| c.1030G>T | G344C 2D AIThe SynGAP1 missense variant G344C is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic outcome include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy methods specifically show pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No tool predicts a benign effect. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD 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 | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -12.880 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 8.52 | Destabilizing | 2.9 | 7.52 | Destabilizing | 8.02 | Destabilizing | 0.59 | Ambiguous | 0.794 | Likely Pathogenic | -8.02 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.47 | Pathogenic | 0.01 | Affected | 0.1184 | 0.4788 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1031G>A | G344D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G344D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Based on the unanimous pathogenic predictions and the absence of benign calls, the variant is most likely pathogenic, 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 | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -12.527 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 14.53 | Destabilizing | 1.5 | 11.36 | Destabilizing | 12.95 | Destabilizing | 1.13 | Destabilizing | 0.897 | Likely Pathogenic | -6.30 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -0.49 | Pathogenic | 0.01 | Affected | 0.1572 | 0.1574 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| 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.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.1045C>G | P349A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions include PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, with the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability or pathogenicity scores are available. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -8.663 | Likely Pathogenic | 0.202 | Likely Benign | Likely Benign | 1.37 | Ambiguous | 0.0 | 1.68 | Ambiguous | 1.53 | Ambiguous | 0.76 | Ambiguous | 0.257 | Likely Benign | -6.01 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.3789 | 0.5505 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1046C>G | P349R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P349R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for P349R. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.167087 | Structured | 0.348607 | Uncertain | 0.947 | 0.396 | 0.000 | -14.001 | Likely Pathogenic | 0.791 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.1 | 2.15 | Destabilizing | 1.57 | Ambiguous | 0.93 | Ambiguous | 0.335 | Likely Benign | -7.22 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 1.55 | Pathogenic | 0.01 | Affected | 0.1395 | 0.3009 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| 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.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.1067G>A | R356H 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R356H is recorded in ClinVar as benign (ClinVar ID 2984966.0) and is present in the gnomAD database (6‑33437972‑G‑A). Prediction tools that indicate a benign effect include REVEL, Rosetta, Foldetta, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, with the SGM‑Consensus also labeling it likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions support a pathogenic impact, which contradicts the ClinVar benign classification. 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 | Likely Benign | 1 | 6-33437972-G-A | 9 | 5.66e-6 | -11.453 | Likely Pathogenic | 0.614 | Likely Pathogenic | Likely Benign | 0.59 | Ambiguous | 0.1 | -0.27 | Likely Benign | 0.16 | Likely Benign | 1.17 | Destabilizing | 0.314 | Likely Benign | -4.43 | Deleterious | 0.999 | Probably Damaging | 0.987 | Probably Damaging | 1.70 | Pathogenic | 0.01 | Affected | 3.39 | 22 | 0.3493 | 0.2206 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||
| c.1079A>C | E360A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E360A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS. All other evaluated tools—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because the majority of consensus tools predict pathogenicity and no ClinVar entry contradicts this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.421183 | Uncertain | 0.955 | 0.498 | 0.250 | -13.229 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 1.37 | Ambiguous | 0.1 | 1.72 | Ambiguous | 1.55 | Ambiguous | 0.39 | Likely Benign | 0.545 | Likely Pathogenic | -5.52 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 1.63 | Pathogenic | 0.01 | Affected | 0.4295 | 0.8243 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1085G>T | W362L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W362L is not reported in ClinVar and is absent from gnomAD. All tools except premPS predict pathogenic, leaving no benign predictions. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. High‑accuracy methods corroborate this assessment: 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. Consequently, the variant is most likely pathogenic, and this prediction 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 | 0.328603 | Structured | 0.430310 | Uncertain | 0.957 | 0.552 | 0.125 | -12.748 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.1 | 2.60 | Destabilizing | 2.38 | Destabilizing | 0.71 | Ambiguous | 0.523 | Likely Pathogenic | -11.95 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.2701 | 0.2452 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||
| 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.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.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.1094T>C | V365A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are made by REVEL and polyPhen‑2 HumVar, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments are consistent with a deleterious outcome: 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) reports a pathogenic effect. Taken together, the majority of evidence supports a pathogenic classification for V365A, 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 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -8.954 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 2.61 | Destabilizing | 0.1 | 2.62 | Destabilizing | 2.62 | Destabilizing | 2.10 | Destabilizing | 0.297 | Likely Benign | -3.18 | Deleterious | 0.622 | Possibly Damaging | 0.235 | Benign | 1.67 | Pathogenic | 0.01 | Affected | 0.2682 | 0.2962 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1102C>A | P368T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P368T missense variant 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, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie (2 benign, 2 pathogenic) and thus inconclusive, and Foldetta remains uncertain. Overall, the predictions are evenly split between benign and pathogenic, providing no definitive classification. The variant’s status does not contradict ClinVar, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.363090 | Structured | 0.439989 | Uncertain | 0.580 | 0.677 | 0.250 | -5.308 | Likely Benign | 0.284 | Likely Benign | Likely Benign | 1.95 | Ambiguous | 0.6 | 1.61 | Ambiguous | 1.78 | Ambiguous | 0.45 | Likely Benign | 0.188 | Likely Benign | -5.43 | Deleterious | 0.941 | Possibly Damaging | 0.527 | Possibly Damaging | 1.72 | Pathogenic | 0.01 | Affected | 0.1983 | 0.6155 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.1117G>A | G373R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G373R is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438022‑G‑A). Prediction tools that classify the variant as benign include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized, and premPS. Those that predict pathogenicity are REVEL, FoldX, Foldetta, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as pathogenic. No prediction or folding result is missing or inconclusive. Overall, the majority of tools (six versus five) and the consensus of high‑accuracy methods lean toward a benign effect. 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. | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | 6-33438022-G-A | 1 | 6.28e-7 | -7.878 | In-Between | 0.653 | Likely Pathogenic | Likely Benign | 4.28 | Destabilizing | 3.5 | 0.14 | Likely Benign | 2.21 | Destabilizing | 0.21 | Likely Benign | 0.510 | Likely Pathogenic | -0.64 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.90 | Benign | 0.01 | Affected | 3.53 | 16 | 0.1089 | 0.4524 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.1117G>C | G373R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G373R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Foldetta, SIFT, and AlphaMissense‑Default; ESM1b 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 pathogenic. Overall, the majority of tools (seven benign vs five pathogenic) lean toward a benign interpretation, 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 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | -7.878 | In-Between | 0.653 | Likely Pathogenic | Likely Benign | 4.28 | Destabilizing | 3.5 | 0.14 | Likely Benign | 2.21 | Destabilizing | 0.21 | Likely Benign | 0.522 | Likely Pathogenic | -0.64 | Neutral | 0.001 | Benign | 0.000 | Benign | 3.90 | Benign | 0.01 | Affected | 3.53 | 16 | 0.1089 | 0.4524 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
| 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.1118G>C | G373A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G373A is not reported in ClinVar and is absent from gnomAD. Functional prediction consensus shows a predominance of benign calls: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict a benign effect. Pathogenic predictions are limited to SIFT and FoldX, while Rosetta and Foldetta yield uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta remains inconclusive. Overall, the majority of evidence indicates that G373A is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | -5.181 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 0.8 | 0.69 | Ambiguous | 1.57 | Ambiguous | -0.01 | Likely Benign | 0.227 | Likely Benign | -0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.93 | Benign | 0.01 | Affected | 0.4172 | 0.5053 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1121C>A | S374Y 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S374Y is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, whereas polyPhen‑2 HumDiv and SIFT predict a pathogenic impact. Uncertain calls come from FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta likewise yields an uncertain stability change. Overall, the majority of available predictions favor a benign effect, and this does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | Uncertain | 1 | -7.774 | In-Between | 0.344 | Ambiguous | Likely Benign | 0.71 | Ambiguous | 1.2 | 0.66 | Ambiguous | 0.69 | Ambiguous | -0.02 | Likely Benign | 0.310 | Likely Benign | -1.18 | Neutral | 0.875 | Possibly Damaging | 0.271 | Benign | 5.41 | Benign | 0.01 | Affected | 4.32 | 13 | 0.1175 | 0.6705 | -3 | -2 | -0.5 | 76.10 | 237.3 | -76.9 | 0.5 | 0.4 | 0.5 | 0.3 | Uncertain | Ser374 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, large and relatively hydrophobic residues like tyrosine are rarely tolerated. Additionally, the hydroxyl group of Tyr374 frequently forms various hydrogen bonds with other loop residues in the variant simulations. Although no negative structural effects are observed in the variant simulations, Tyr374 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.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.1126G>T | G376C 2D AISynGAP1 missense variant G376C is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from Rosetta, premPS, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls come from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools report uncertainty: Foldetta and ESM1b. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign verdict; Foldetta remains uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, whereas the most accurate methods favor a benign effect. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | Uncertain | 1 | -7.686 | In-Between | 0.125 | Likely Benign | Likely Benign | 2.56 | Destabilizing | 0.5 | 0.22 | Likely Benign | 1.39 | Ambiguous | 0.16 | Likely Benign | 0.560 | Likely Pathogenic | -1.15 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1476 | 0.3929 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||
| c.1127G>T | G376V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G376V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions arise from REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The consensus score from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, matching the majority of individual benign calls. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, SGM Consensus predicts benign, whereas Foldetta (integrating FoldX‑MD and Rosetta) predicts pathogenic. No prediction is missing or inconclusive. Overall, the balance of evidence leans toward a benign effect; this is consistent with the lack of ClinVar annotation and gnomAD presence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | -6.242 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 4.84 | Destabilizing | 0.8 | -0.81 | Ambiguous | 2.02 | Destabilizing | -0.18 | Likely Benign | 0.541 | Likely Pathogenic | -0.66 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1594 | 0.3525 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.1132G>T | G378C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Overall, the majority of tools (8/12) predict pathogenicity, and the high‑accuracy consensus leans toward benign only for AlphaMissense‑Optimized and SGM Consensus, while Foldetta indicates instability. Thus, the variant is most likely pathogenic based on the preponderance of evidence, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -7.981 | In-Between | 0.203 | Likely Benign | Likely Benign | 7.63 | Destabilizing | 2.7 | 12.14 | Destabilizing | 9.89 | Destabilizing | 0.26 | Likely Benign | 0.635 | Likely Pathogenic | -1.18 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1595 | 0.4240 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1136C>G | S379W 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379W is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438041‑C‑G). Prediction tools that indicate a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus as benign. Because the majority of conventional tools favor pathogenicity while the high‑accuracy subset is split, the overall evidence leans toward a pathogenic effect. This conclusion does not contradict the ClinVar uncertain status, which remains unresolved. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | Uncertain | 1 | 6-33438041-C-G | -8.898 | Likely Pathogenic | 0.388 | Ambiguous | Likely Benign | 4.32 | Destabilizing | 3.4 | 3.56 | Destabilizing | 3.94 | Destabilizing | 0.16 | Likely Benign | 0.520 | Likely Pathogenic | -1.02 | Neutral | 0.998 | Probably Damaging | 0.844 | Possibly Damaging | 3.82 | Benign | 0.01 | Affected | 4.32 | 11 | 0.1196 | 0.6070 | -2 | -3 | -0.1 | 99.14 | 271.3 | -75.7 | 1.4 | 1.0 | 0.6 | 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 tryptophan are rarely tolerated. Although no major negative structural effects are observed in the variant simulations, Trp379 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.1138G>A | G380R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G380R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain. 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 due to a 2‑vs‑2 split. Overall, the majority of evidence (10 pathogenic vs. 4 benign) points to a pathogenic impact. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.205 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 5.94 | Destabilizing | 2.6 | 0.90 | Ambiguous | 3.42 | Destabilizing | 0.11 | Likely Benign | 0.640 | Likely Pathogenic | -0.86 | Neutral | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 2.53 | Benign | 0.01 | Affected | 0.1319 | 0.3956 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1138G>C | G380R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G380R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that agree on a pathogenic effect are REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, Foldetta predicts pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of tools (10 pathogenic vs 4 benign) and the Foldetta result 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. | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -9.205 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 5.94 | Destabilizing | 2.6 | 0.90 | Ambiguous | 3.42 | Destabilizing | 0.11 | Likely Benign | 0.619 | Likely Pathogenic | -0.86 | Neutral | 0.940 | Possibly Damaging | 0.459 | Possibly Damaging | 2.53 | Benign | 0.01 | Affected | 0.1319 | 0.3956 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||
| c.1141G>T | G381W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381W is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438046‑G‑T). Prediction tools that agree on a benign effect include premPS, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments give AlphaMissense‑Optimized a benign call, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic call, and Foldetta (combining FoldX‑MD and Rosetta outputs) a pathogenic call. No prediction or folding result is missing or inconclusive. Overall, the majority of tools and the high‑accuracy methods indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment 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 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438046-G-T | 1 | 6.24e-7 | -10.173 | Likely Pathogenic | 0.438 | Ambiguous | Likely Benign | 8.81 | Destabilizing | 2.0 | 3.17 | Destabilizing | 5.99 | Destabilizing | 0.02 | Likely Benign | 0.576 | Likely Pathogenic | -1.04 | Neutral | 0.996 | Probably Damaging | 0.920 | Probably Damaging | 1.31 | Pathogenic | 0.01 | Affected | 4.32 | 9 | 0.0993 | 0.4000 | -2 | -7 | -0.5 | 129.16 | |||||||||||||||||||||||||
| c.1148G>A | G383E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Tools that predict a pathogenic effect are FoldX, Rosetta, SIFT, ESM1b, AlphaMissense‑Default, and the protein‑folding stability method Foldetta. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (benign), is inconclusive (tie). Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a pathogenic effect. Overall, the majority of predictions (seven pathogenic vs. six benign) indicate 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. | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -9.535 | Likely Pathogenic | 0.570 | Likely Pathogenic | Likely Benign | 4.09 | Destabilizing | 2.4 | 2.62 | Destabilizing | 3.36 | Destabilizing | 0.39 | Likely Benign | 0.308 | Likely Benign | -0.78 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.10 | Benign | 0.01 | Affected | 0.1582 | 0.3741 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||
| 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.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.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.1154C>T | S385L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438059‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus itself is benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of computational evidence indicates the variant is most likely benign, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | Uncertain | 2 | 6-33438059-C-T | 9 | 4.60e-5 | -6.018 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.1 | 0.08 | Likely Benign | 0.12 | Likely Benign | -0.26 | Likely Benign | 0.304 | Likely Benign | -0.68 | Neutral | 0.829 | Possibly Damaging | 0.706 | Possibly Damaging | 4.63 | Benign | 0.01 | Affected | 4.32 | 3 | 0.1897 | 0.6244 | -3 | -2 | 4.6 | 26.08 | 244.6 | -50.1 | 0.0 | 0.6 | -0.1 | 0.1 | Uncertain | Ser385 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, Leu385 may exert drastic effects on the SynGAP-membrane complex dynamics and stability. However, since the effects on Gly-rich Ω loop dynamics can only be studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||
| 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.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.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.1159G>C | G387R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G387R 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 premPS, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Tools that predict pathogenicity are SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign effect, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are missing or inconclusive. Overall, the majority of evidence (10 pathogenic vs. 4 benign) indicates 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 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | -8.728 | Likely Pathogenic | 0.683 | Likely Pathogenic | Likely Benign | 4.13 | Destabilizing | 2.9 | 2.57 | Destabilizing | 3.35 | Destabilizing | 0.15 | Likely Benign | 0.516 | Likely Pathogenic | -0.54 | Neutral | 0.003 | Benign | 0.004 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 0.1309 | 0.4356 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||
| 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.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.1162G>T | G388C 2D 3DClick to see structure in 3D Viewer AISynGAP1 G388C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from AlphaMissense‑Default, AlphaMissense‑Optimized, premPS, and PROVEAN, while pathogenic predictions arise from REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized predicts benign, Foldetta predicts pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Because the majority of evidence points to pathogenicity and there is no ClinVar entry to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | -8.088 | Likely Pathogenic | 0.121 | Likely Benign | Likely Benign | 4.01 | Destabilizing | 3.7 | 4.95 | Destabilizing | 4.48 | Destabilizing | 0.03 | Likely Benign | 0.603 | Likely Pathogenic | -0.98 | Neutral | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1497 | 0.4112 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||
| c.1163G>T | G388V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388V is catalogued in gnomAD (6-33438068-G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Pathogenic predictions arise from REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized remains benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign, whereas Foldetta—combining FoldX‑MD and Rosetta stability outputs—labels the variant as pathogenic. Overall, the majority of tools and the Foldetta result point to a pathogenic effect. This conclusion does not conflict with ClinVar, which currently contains no classification for G388V. 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 | 6-33438068-G-T | -6.887 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 6.58 | Destabilizing | 6.6 | 5.51 | Destabilizing | 6.05 | Destabilizing | -0.11 | Likely Benign | 0.620 | Likely Pathogenic | -0.93 | Neutral | 0.994 | Probably Damaging | 0.990 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 4.32 | 3 | 0.1600 | 0.3897 | -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.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.1169G>T | G390V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G390V has no ClinVar entry and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, FoldX, Rosetta, Foldetta, SIFT, and FATHMM, while ESM1b remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default (benign), ESM1b (uncertain), FATHMM (pathogenic), and PROVEAN (benign), also yields a benign verdict; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, indicates pathogenic. With two high‑accuracy tools supporting benign and one supporting pathogenic, the overall evidence leans toward a benign effect. This conclusion does not contradict ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -7.137 | In-Between | 0.146 | Likely Benign | Likely Benign | 3.74 | Destabilizing | 0.6 | 4.88 | Destabilizing | 4.31 | Destabilizing | -0.16 | Likely Benign | 0.509 | Likely Pathogenic | -0.88 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.32 | Pathogenic | 0.01 | Affected | 0.1537 | 0.4004 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||
| c.1177G>T | G393C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G393C is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Rosetta, premPS, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus (likely pathogenic), REVEL, FoldX, 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 as uncertain (no definitive stability change). The majority of evidence points toward a pathogenic effect, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -8.854 | Likely Pathogenic | 0.181 | Likely Benign | Likely Benign | 2.99 | Destabilizing | 0.9 | -0.26 | Likely Benign | 1.37 | Ambiguous | 0.43 | Likely Benign | 0.769 | Likely Pathogenic | -3.05 | Deleterious | 0.999 | Probably Damaging | 0.936 | Probably Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1593 | 0.4408 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1178G>T | G393V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G393V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Rosetta is uncertain and is treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while Foldetta predicts pathogenic. The SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑vs‑2 split. Overall, the majority of evidence (8 pathogenic vs. 4 benign) points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -6.358 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 5.56 | Destabilizing | 2.3 | -0.72 | Ambiguous | 2.42 | Destabilizing | -0.01 | Likely Benign | 0.639 | Likely Pathogenic | -2.69 | Deleterious | 0.982 | Probably Damaging | 0.648 | Possibly Damaging | 1.32 | Pathogenic | 0.01 | Affected | 0.1712 | 0.4144 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||
| c.1180A>C | K394Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394Q 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, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic outcome are SIFT and Rosetta. The remaining tools—Foldetta, premPS, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also leans toward benign, with two benign votes and two uncertain votes. Foldetta’s stability prediction is uncertain and thus not considered. Overall, the majority of reliable predictions indicate a benign effect, 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 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.261 | In-Between | 0.468 | Ambiguous | Likely Benign | 0.15 | Likely Benign | 0.0 | 2.00 | Destabilizing | 1.08 | Ambiguous | 0.64 | Ambiguous | 0.330 | Likely Benign | -2.46 | Neutral | 0.001 | Benign | 0.009 | Benign | 4.61 | Benign | 0.01 | Affected | 0.5365 | 0.2106 | Weaken | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| 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.1182A>C | K394N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394N 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, FATHMM, and polyPhen‑2 HumVar. Those that agree on a pathogenic effect are Rosetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive are Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, Foldetta as uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.408 | In-Between | 0.861 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.1 | 2.02 | Destabilizing | 1.05 | Ambiguous | 0.66 | Ambiguous | 0.299 | Likely Benign | -3.17 | Deleterious | 0.535 | Possibly Damaging | 0.188 | Benign | 4.60 | Benign | 0.01 | Affected | 0.4353 | 0.2654 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.1182A>T | K394N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K394N missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a mixed signal: benign calls come from REVEL, FoldX, FATHMM, and polyPhen‑2 HumVar, while pathogenic calls come from Rosetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. Four tools (Foldetta, premPS, ESM1b, AlphaMissense‑Optimized) return uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic; and Foldetta is uncertain. Taken together, the majority of evidence—including the high‑accuracy consensus—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. | C2 | 0.505461 | Disordered | 0.399336 | Uncertain | 0.387 | 0.634 | 0.625 | -7.408 | In-Between | 0.861 | Likely Pathogenic | Ambiguous | 0.08 | Likely Benign | 0.1 | 2.02 | Destabilizing | 1.05 | Ambiguous | 0.66 | Ambiguous | 0.299 | Likely Benign | -3.17 | Deleterious | 0.535 | Possibly Damaging | 0.188 | Benign | 4.60 | Benign | 0.01 | Affected | 0.4353 | 0.2654 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.1192C>A | P398T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P398T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, and SIFT. The remaining tools (Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain results. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta is uncertain. Overall, the majority of high‑confidence predictions lean toward a benign impact, although several other predictors indicate pathogenicity. There is no conflict with ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | -6.670 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 2.11 | Destabilizing | 0.4 | 1.57 | Ambiguous | 1.84 | Ambiguous | 0.78 | Ambiguous | 0.608 | Likely Pathogenic | -5.70 | Deleterious | 0.816 | Possibly Damaging | 0.307 | Benign | 5.51 | Benign | 0.01 | Affected | 0.1671 | 0.6607 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.1193C>T | P398L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P398L (ClinVar ID 2415189.0) is listed as Uncertain in ClinVar and is present in gnomAD (ID 6‑33438098‑C‑T). Functional prediction tools that agree on a benign effect include Foldetta, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and SIFT. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.436924 | Structured | 0.401041 | Uncertain | 0.891 | 0.525 | 0.250 | Uncertain | 1 | 6-33438098-C-T | 8 | 4.96e-6 | -7.518 | In-Between | 0.547 | Ambiguous | Likely Benign | 1.48 | Ambiguous | 0.2 | -0.54 | Ambiguous | 0.47 | Likely Benign | 0.62 | Ambiguous | 0.599 | Likely Pathogenic | -7.10 | Deleterious | 0.961 | Probably Damaging | 0.256 | Benign | 5.72 | Benign | 0.01 | Affected | 3.40 | 16 | 0.2248 | 0.7157 | -3 | -3 | 5.4 | 16.04 | 245.8 | -68.6 | -0.1 | 0.0 | -0.3 | 0.2 | X | Potentially Pathogenic | Pro398 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. Although the residue swap does not influence the nearby secondary structure elements, proline is often found at the ends of β sheets due to its disfavored status during folding.Additionally, 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 significant roles in protein functions that require flexibility, and thus hydrophobic residues like leucine are rarely tolerated. Although no negative structural effects are visualized in the variant’s simulations, Leu398 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.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.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.1205T>C | L402P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L402P is not reported in ClinVar and is absent from gnomAD. Consensus among in‑silico predictors is overwhelmingly pathogenic: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect, whereas only FATHMM predicts a benign outcome. High‑accuracy tools reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Taken together, the evidence strongly supports a pathogenic classification, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -12.030 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 7.40 | Destabilizing | 0.1 | 5.82 | Destabilizing | 6.61 | Destabilizing | 2.22 | Destabilizing | 0.616 | Likely Pathogenic | -4.80 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 3.68 | Benign | 0.01 | Affected | 0.3628 | 0.1874 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1207A>C | K403Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. The premPS assessment is uncertain and does not influence the overall consensus. High‑accuracy analyses show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -12.479 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.36 | Likely Benign | 0.0 | 0.27 | Likely Benign | 0.32 | Likely Benign | 0.70 | Ambiguous | 0.376 | Likely Benign | -3.59 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 3.76 | Benign | 0.01 | Affected | 0.4405 | 0.1954 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1208A>C | K403T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K403T missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; SGM‑Consensus predicts likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also uncertain. Overall, the consensus of the majority of tools indicates a pathogenic effect. This conclusion is not contradicted by ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.424920 | Uncertain | 0.960 | 0.372 | 0.000 | -13.135 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.41 | Ambiguous | 0.1 | 0.59 | Ambiguous | 1.00 | Ambiguous | 0.67 | Ambiguous | 0.522 | Likely Pathogenic | -5.43 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.73 | Benign | 0.01 | Affected | 0.1861 | 0.4230 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| 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.1214G>A | R405H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R405H is listed in ClinVar with an uncertain significance (ClinVar ID 863440.0) and is present in gnomAD (variant ID 6‑33438119‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized reports a benign change, whereas the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta) both predict pathogenicity. Overall, the preponderance of evidence indicates that R405H is most likely pathogenic, which does not contradict the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Conflicting | 2 | 6-33438119-G-A | 4 | 2.48e-6 | -9.081 | Likely Pathogenic | 0.706 | Likely Pathogenic | Likely Benign | 2.79 | Destabilizing | 0.6 | 1.85 | Ambiguous | 2.32 | Destabilizing | 1.26 | Destabilizing | 0.371 | Likely Benign | -4.54 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.65 | Benign | 0.01 | Affected | 3.38 | 28 | 0.3395 | 0.2363 | 2 | 0 | 1.3 | -19.05 | 214.0 | 102.2 | -0.1 | 0.0 | -0.7 | 0.1 | X | Potentially Pathogenic | The guanidinium group of Arg405, located in an anti-parallel β sheet strand of the C2 domain (res. Pro398-Ile411), forms a salt bridge with the carboxylate group of the Glu446 side chain from an opposing α helix (res. Val441-Ser457) in the GAP domain. The positively charged Arg405 side chain also stacks with the aromatic ring of the Phe358 side chain from a loop preceding the β strand (res. Thr359-Thr366), which could assist in maintaining the anti-parallel strand arrangement.In the variant simulations, the imidazole ring of His405 does not stack with the aromatic ring of Phe358 nor form any lasting H-bonds with the loop residues. The imidazole ring of His405 (neutral and epsilon protonated in the simulations) is unable to form a salt bridge with Glu446, which could affect the tertiary structure assembly, although this is not apparent based on the variant simulations. | |||||||||||||
| c.1214G>C | R405P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R405P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates it is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies it as pathogenic. Based on the overwhelming agreement among these predictions, the variant is most likely pathogenic, which does not contradict its current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | Uncertain | 1 | -14.206 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.11 | Destabilizing | 0.3 | 5.19 | Destabilizing | 4.15 | Destabilizing | 1.26 | Destabilizing | 0.572 | Likely Pathogenic | -6.32 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.62 | Benign | 0.01 | Affected | 3.38 | 28 | 0.2140 | 0.5138 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||
| c.1214G>T | R405L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R405L missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are Rosetta and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) indicate a pathogenic or likely pathogenic impact. Uncertain results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta providing an inconclusive stability prediction. Overall, the preponderance of evidence points to a pathogenic effect for R405L, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.250310 | Structured | 0.404888 | Uncertain | 0.949 | 0.315 | 0.000 | -11.576 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 1.43 | Ambiguous | 0.7 | 0.40 | Likely Benign | 0.92 | Ambiguous | 0.72 | Ambiguous | 0.512 | Likely Pathogenic | -6.35 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.64 | Benign | 0.01 | Affected | 0.2126 | 0.5555 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.1216T>G | Y406D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and FATHMM. In contrast, the majority of tools predict a pathogenic impact: FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” while premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the preponderance of evidence, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -14.832 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.82 | Destabilizing | 0.3 | 4.28 | Destabilizing | 4.05 | Destabilizing | 0.98 | Ambiguous | 0.347 | Likely Benign | -7.64 | Deleterious | 0.999 | Probably Damaging | 0.950 | Probably Damaging | 3.77 | Benign | 0.01 | Affected | 0.4439 | 0.0903 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1217A>G | Y406C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y406C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict a pathogenic impact: FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome, and the Foldetta stability assessment (combining FoldX‑MD and Rosetta) predicts a destabilizing, pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while both SGM‑Consensus and Foldetta are pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for Y406C, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.393707 | Uncertain | 0.946 | 0.291 | 0.000 | -9.954 | Likely Pathogenic | 0.810 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 0.2 | 3.22 | Destabilizing | 2.85 | Destabilizing | 1.27 | Destabilizing | 0.229 | Likely Benign | -6.72 | Deleterious | 0.998 | Probably Damaging | 0.851 | Possibly Damaging | 3.78 | Benign | 0.01 | Affected | 0.3026 | 0.2861 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.1221G>C | Q407H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q407H (C2 domain) has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools predict pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | -10.526 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.59 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.60 | Ambiguous | 1.10 | Destabilizing | 0.206 | Likely Benign | -4.51 | Deleterious | 0.982 | Probably Damaging | 0.947 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 3.38 | 28 | 0.1205 | 0.3154 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||
| c.1221G>T | Q407H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q407H is listed in ClinVar with an uncertain significance (ClinVar ID 2772184.0) and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions marked as uncertain include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for Q407H. This conclusion does not conflict with the ClinVar designation of uncertain significance, which remains unresolved pending further evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.109221 | Structured | 0.382522 | Uncertain | 0.916 | 0.271 | 0.000 | Uncertain | 1 | -10.526 | Likely Pathogenic | 0.830 | Likely Pathogenic | Ambiguous | 0.59 | Ambiguous | 0.0 | 0.61 | Ambiguous | 0.60 | Ambiguous | 1.10 | Destabilizing | 0.206 | Likely Benign | -4.51 | Deleterious | 0.982 | Probably Damaging | 0.947 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 3.38 | 28 | 0.1205 | 0.3154 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||
| c.1231A>C | I411L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I411L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas a majority (premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Tools with uncertain or mixed outputs are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, yielding no definitive call; and Foldetta also reports an uncertain stability change. Overall, the majority of standard predictors lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational evidence, though high‑accuracy tools remain inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.339366 | Uncertain | 0.927 | 0.198 | 0.000 | -10.723 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 1.02 | Ambiguous | 0.3 | 1.89 | Ambiguous | 1.46 | Ambiguous | 1.17 | Destabilizing | 0.285 | Likely Benign | -1.84 | Neutral | 0.908 | Possibly Damaging | 0.943 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 0.0876 | 0.3539 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1234T>G | L412V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L412V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the remaining tools—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.122885 | Structured | 0.331108 | Uncertain | 0.937 | 0.196 | 0.000 | -11.726 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.0 | 3.52 | Destabilizing | 3.59 | Destabilizing | 1.54 | Destabilizing | 0.231 | Likely Benign | -2.76 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 3.25 | Benign | 0.01 | Affected | 0.1275 | 0.3378 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1237C>A | P413T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P413T missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this view: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -12.851 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.22 | Destabilizing | 0.2 | 1.87 | Ambiguous | 2.55 | Destabilizing | 0.93 | Ambiguous | 0.554 | Likely Pathogenic | -7.37 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.18 | Benign | 0.01 | Affected | 0.1663 | 0.4670 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.1238C>G | P413R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P413R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The remaining methods, Foldetta and Rosetta, yield uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.332472 | Uncertain | 0.927 | 0.201 | 0.000 | -15.523 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.40 | Destabilizing | 0.2 | 1.34 | Ambiguous | 1.87 | Ambiguous | 1.07 | Destabilizing | 0.562 | Likely Pathogenic | -8.29 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | 0.1550 | 0.2199 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| 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.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.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.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.1265A>C | E422A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E422A missense variant is not reported in ClinVar and has no gnomAD entry. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized remains uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is inconclusive; the SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates likely pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the balance of evidence (seven pathogenic versus six benign predictions) points to a likely pathogenic effect for E422A, and this conclusion is not contradicted by the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -12.088 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.37 | Likely Benign | 0.26 | Likely Benign | 0.371 | Likely Benign | -5.43 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.2949 | 0.4459 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1265A>G | E422G 2D 3DClick to see structure in 3D Viewer AISynGAP1 E422G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, premPS, and FATHMM, while pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are provided by FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy analyses indicate that the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts a likely pathogenic effect, whereas AlphaMissense‑Optimized remains inconclusive and Foldetta shows no definitive stability change. Overall, the majority of evidence points toward a pathogenic impact for E422G, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.426709 | Uncertain | 0.965 | 0.255 | 0.000 | -11.468 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 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.1270G>T | V424F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V424F is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Optimized) yield uncertain or unavailable results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -10.947 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 1.99 | Ambiguous | 0.3 | -0.37 | Likely Benign | 0.81 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -3.66 | Deleterious | 0.995 | Probably Damaging | 0.775 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.0816 | 0.2094 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.1271T>C | V424A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V424A is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as unavailable, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. Based on the collective evidence, the variant is most likely pathogenic; this conclusion is not contradicted by the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -9.665 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 2.31 | Destabilizing | 0.1 | 2.54 | Destabilizing | 2.43 | Destabilizing | 2.10 | Destabilizing | 0.245 | Likely Benign | -3.45 | Deleterious | 0.997 | Probably Damaging | 0.961 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.2105 | 0.1355 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1279C>T | H427Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H427Y missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar, as well as the SGM‑Consensus “Likely Benign” call. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, and SIFT. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly indicate a benign effect. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -6.824 | Likely Benign | 0.328 | Likely Benign | Likely Benign | -0.08 | Likely Benign | 0.0 | -0.37 | Likely Benign | -0.23 | Likely Benign | 0.18 | Likely Benign | 0.180 | Likely Benign | -3.47 | Deleterious | 0.815 | Possibly Damaging | 0.073 | Benign | 3.44 | Benign | 0.01 | Affected | 0.0958 | 0.4029 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||
| c.1280A>C | H427P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H427P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas the majority of tools (FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Two tools are uncertain: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both indicate a pathogenic effect. Overall, the preponderance of evidence points to a pathogenic classification for H427P, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -11.098 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 4.74 | Destabilizing | 0.1 | 7.61 | Destabilizing | 6.18 | Destabilizing | 0.68 | Ambiguous | 0.324 | Likely Benign | -4.22 | Deleterious | 0.993 | Probably Damaging | 0.819 | Possibly Damaging | 3.51 | Benign | 0.01 | Affected | 0.2061 | 0.3442 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1280A>T | H427L 2D 3DClick to see structure in 3D Viewer AISynGAP1 H427L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: nine tools (REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while five tools (SGM‑Consensus, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default) predict pathogenicity. High‑accuracy methods provide a more focused view: AlphaMissense‑Optimized indicates a benign outcome; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, remains pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Taken together, the majority of evidence supports a benign impact for H427L, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.081712 | Structured | 0.394261 | Uncertain | 0.962 | 0.287 | 0.000 | -9.691 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | -0.17 | Likely Benign | 0.0 | 0.05 | Likely Benign | -0.06 | Likely Benign | 0.31 | Likely Benign | 0.272 | Likely Benign | -5.38 | Deleterious | 0.299 | Benign | 0.033 | Benign | 3.42 | Benign | 0.01 | Affected | 0.0942 | 0.4953 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.1282T>G | Y428D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Y428D is not reported in ClinVar and is absent from gnomAD. Across a broad panel of in silico predictors, 15 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly predict a deleterious effect, whereas only FATHMM classifies it as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic effect. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.389652 | Uncertain | 0.965 | 0.292 | 0.000 | -13.473 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.24 | Destabilizing | 0.0 | 4.19 | Destabilizing | 3.72 | Destabilizing | 1.64 | Destabilizing | 0.554 | Likely Pathogenic | -9.55 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.50 | Benign | 0.01 | Affected | 0.4458 | 0.1003 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| 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.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.1294T>C | C432R 2D 3DClick to see structure in 3D Viewer AIClinVar has no entry for this SynGAP1 missense variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM. The majority of algorithms predict a pathogenic impact: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). FoldX and Foldetta report uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, while Foldetta remains inconclusive. Overall, the consensus of the available predictions indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.111485 | Structured | 0.362533 | Uncertain | 0.960 | 0.285 | 0.000 | -13.858 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.03 | Ambiguous | 0.2 | 2.05 | Destabilizing | 1.54 | Ambiguous | 1.73 | Destabilizing | 0.690 | Likely Pathogenic | -11.46 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0.1359 | 0.1766 | -4 | -3 | -7.0 | 53.05 | |||||||||||||||||||||||||||||
| 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.1303T>A | L435M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L435M missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -4.705 | Likely Benign | 0.534 | Ambiguous | Likely Benign | 0.24 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.63 | Ambiguous | 1.05 | Destabilizing | 0.233 | Likely Benign | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.17 | Benign | 0.01 | Affected | 0.0675 | 0.2753 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.1304T>C | L435S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -12.662 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 4.18 | Destabilizing | 0.0 | 4.09 | Destabilizing | 4.14 | Destabilizing | 1.83 | Destabilizing | 0.596 | Likely Pathogenic | -5.63 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.18 | Benign | 0.01 | Affected | 0.2705 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.1305G>C | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of any ClinVar annotation to contradict this assessment, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | 0.222 | Likely Benign | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0587 | 0.2723 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1305G>T | L435F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L435F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (Likely Pathogenic). High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain, providing no definitive evidence for either outcome. Given the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.229226 | Structured | 0.333584 | Uncertain | 0.954 | 0.292 | 0.000 | -11.871 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.1 | 0.95 | Ambiguous | 0.73 | Ambiguous | 0.69 | Ambiguous | 0.222 | Likely Benign | -3.75 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0587 | 0.2723 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1306G>C | E436Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E436Q is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include premPS and FATHMM, while the majority of tools predict a pathogenic outcome: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the consensus of pathogenic predictions outweighs benign ones, and the high‑accuracy tools reinforce a pathogenic classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -12.413 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.1 | 1.58 | Ambiguous | 1.05 | Ambiguous | 0.50 | Likely Benign | 0.607 | Likely Pathogenic | -2.76 | Deleterious | 0.992 | Probably Damaging | 0.946 | Probably Damaging | 4.64 | Benign | 0.01 | Affected | 0.1237 | 0.5809 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1308G>C | E436D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are limited to FATHMM, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic (3 pathogenic vs. 1 benign). Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -10.355 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.55 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.63 | Ambiguous | 0.73 | Ambiguous | 0.554 | Likely Pathogenic | -2.85 | Deleterious | 0.986 | Probably Damaging | 0.921 | Probably Damaging | 4.61 | Benign | 0.01 | Affected | 0.1938 | 0.3553 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1308G>T | E436D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E436D missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two groups: benign predictions are limited to FATHMM, while the remaining nine tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict pathogenicity. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain results and are treated as unavailable. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also pathogenic (3 pathogenic vs. 1 benign). Foldetta’s stability prediction is uncertain. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.239899 | Structured | 0.321046 | Uncertain | 0.934 | 0.289 | 0.000 | -10.355 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.55 | Ambiguous | 0.1 | 0.71 | Ambiguous | 0.63 | Ambiguous | 0.73 | Ambiguous | 0.554 | Likely Pathogenic | -2.85 | Deleterious | 0.986 | Probably Damaging | 0.921 | Probably Damaging | 4.61 | Benign | 0.01 | Affected | 0.1938 | 0.3553 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.1309C>A | P437T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P437T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting pathogenic, and Foldetta yielding an uncertain stability change. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.011 | Likely Pathogenic | 0.484 | Ambiguous | Likely Benign | 1.35 | Ambiguous | 0.0 | -3.46 | Stabilizing | -1.06 | Ambiguous | 0.54 | Ambiguous | 0.305 | Likely Benign | -6.67 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0.1659 | 0.5782 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.1309C>T | P437S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P437S is not reported in ClinVar (ClinVar ID: None) but is present in gnomAD (ID 6‑33438214‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b all predict a pathogenic outcome; the remaining methods (FoldX, Foldetta, premPS, AlphaMissense‑Default) are uncertain and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the balance of evidence favors a pathogenic interpretation. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | 6-33438214-C-T | 2 | 1.24e-6 | -11.964 | Likely Pathogenic | 0.518 | Ambiguous | Likely Benign | 1.14 | Ambiguous | 0.0 | -3.31 | Stabilizing | -1.09 | Ambiguous | 0.60 | Ambiguous | 0.226 | Likely Benign | -6.60 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.49 | Benign | 0.01 | Affected | 3.38 | 26 | 0.3548 | 0.4843 | -1 | 1 | 0.8 | -10.04 | |||||||||||||||||||||||||
| c.1310C>A | P437H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P437H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, and FATHMM, whereas those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive or unavailable are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the balance of evidence favors a pathogenic classification for P437H, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.306196 | Uncertain | 0.921 | 0.298 | 0.000 | -13.496 | Likely Pathogenic | 0.826 | Likely Pathogenic | Ambiguous | 1.19 | Ambiguous | 0.0 | -3.28 | Stabilizing | -1.05 | Ambiguous | 0.31 | Likely Benign | 0.343 | Likely Benign | -7.75 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 3.44 | Benign | 0.01 | Affected | 0.1819 | 0.4328 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||
| c.1316T>A | L439Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -11.162 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 2.50 | Destabilizing | 0.1 | 2.06 | Destabilizing | 2.28 | Destabilizing | 1.35 | Destabilizing | 0.575 | Likely Pathogenic | -5.15 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0.1065 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1316T>G | L439R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L439R lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the remaining evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic or likely pathogenic impact; FoldX is uncertain and is treated as unavailable. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -12.870 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.90 | Ambiguous | 0.5 | 2.62 | Destabilizing | 2.26 | Destabilizing | 1.40 | Destabilizing | 0.554 | Likely Pathogenic | -5.25 | Deleterious | 0.996 | Probably Damaging | 0.983 | Probably Damaging | 3.22 | Benign | 0.01 | Affected | 0.1217 | 0.0488 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1330A>G | K444E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K444E missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated predictors—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -15.571 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.99 | Destabilizing | 0.1 | 3.75 | Destabilizing | 3.37 | Destabilizing | 1.10 | Destabilizing | 0.437 | Likely Benign | -3.82 | Deleterious | 0.997 | Probably Damaging | 0.981 | Probably Damaging | 3.40 | Benign | 0.01 | Affected | 0.3486 | 0.0793 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.1331A>C | K444T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Foldetta, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain (treated as unavailable for pathogenicity inference). Overall, the majority of reliable predictions indicate a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -15.557 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 2.12 | Destabilizing | 0.1 | 1.17 | Ambiguous | 1.65 | Ambiguous | 0.96 | Ambiguous | 0.442 | Likely Benign | -5.73 | Deleterious | 0.999 | Probably Damaging | 1.000 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0.1643 | 0.3416 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.1332G>C | K444N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the majority of tools (FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; Foldetta’s stability assessment is uncertain and therefore not used as evidence. Overall, the preponderance of evidence points to a pathogenic effect for K444N. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.797 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | 0.286 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3282 | 0.1213 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1332G>T | K444N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K444N is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that predict a pathogenic effect include FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.203355 | Structured | 0.262172 | Uncertain | 0.955 | 0.213 | 0.000 | -14.797 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.41 | Destabilizing | 0.0 | 1.52 | Ambiguous | 1.97 | Ambiguous | 1.18 | Destabilizing | 0.286 | Likely Benign | -4.77 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3282 | 0.1213 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.1334A>C | E445A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as Benign. Overall, the majority of predictions lean toward pathogenicity, and the high‑accuracy consensus supports a likely pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -12.659 | Likely Pathogenic | 0.849 | Likely Pathogenic | Ambiguous | 0.09 | Likely Benign | 0.0 | -0.34 | Likely Benign | -0.13 | Likely Benign | 0.56 | Ambiguous | 0.476 | Likely Benign | -5.73 | Deleterious | 0.997 | Probably Damaging | 0.991 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | 0.2846 | 0.4876 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1334A>G | E445G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, while the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Predictions that are inconclusive or uncertain are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E445G, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -12.294 | Likely Pathogenic | 0.823 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.1 | 0.79 | Ambiguous | 0.80 | Ambiguous | 0.69 | Ambiguous | 0.523 | Likely Pathogenic | -6.68 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.2446 | 0.4202 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1334A>T | E445V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E445V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Two tools give uncertain results: Rosetta and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of evidence points toward a pathogenic effect. The variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.270205 | Uncertain | 0.947 | 0.228 | 0.000 | -14.830 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.17 | Likely Benign | 0.32 | Likely Benign | 0.572 | Likely Pathogenic | -6.68 | Deleterious | 0.992 | Probably Damaging | 0.967 | Probably Damaging | 3.34 | Benign | 0.01 | Affected | 0.0414 | 0.5233 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1336G>A | E446K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E446K is not reported in ClinVar (ClinVar status: not present) and is found in gnomAD (ID 6‑33438241‑G‑A). Prediction tools that agree on a benign effect include only FATHMM. Tools that agree on a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote). Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy methods give the following: AlphaMissense‑Optimized is uncertain; SGM‑Consensus indicates likely pathogenic; Foldetta is uncertain. Overall, the majority of evidence points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.276479 | Uncertain | 0.940 | 0.216 | 0.000 | 6-33438241-G-A | 1 | 6.19e-7 | -14.140 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.4 | 1.57 | Ambiguous | 1.19 | Ambiguous | 0.81 | Ambiguous | 0.518 | Likely Pathogenic | -3.75 | Deleterious | 0.994 | Probably Damaging | 0.975 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 3.38 | 31 | 0.2141 | 0.6511 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.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.1340T>A | V447D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V447D lies in the GAP domain. ClinVar has no entry for this change, and it is absent from gnomAD. Prediction tools that agree on benign impact are REVEL and FATHMM, whereas the remaining predictors—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classify the variant as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta also reports a pathogenic effect. Overall, the evidence points to a pathogenic effect for V447D, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -16.643 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.34 | Destabilizing | 0.1 | 3.59 | Destabilizing | 3.97 | Destabilizing | 2.29 | Destabilizing | 0.491 | Likely Benign | -5.33 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.1424 | 0.0541 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.1340T>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.1342G>C | A448P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A448P is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that assess pathogenicity largely agree: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect, while only FATHMM predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized returns a pathogenic prediction; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a likely pathogenic result; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.292774 | Uncertain | 0.973 | 0.257 | 0.000 | -13.706 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.42 | Destabilizing | 0.0 | 8.74 | Destabilizing | 7.08 | Destabilizing | 1.16 | Destabilizing | 0.650 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 0.1758 | 0.3626 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1351C>G | L451V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451V is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. In contrast, the majority of tools predict a pathogenic impact: SGM‑Consensus (Likely Pathogenic), FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta is uncertain and does not contribute to the consensus. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic; and Foldetta predicts pathogenic. Overall, the preponderance of evidence points to a pathogenic effect for L451V. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -10.732 | Likely Pathogenic | 0.635 | Likely Pathogenic | Likely Benign | 2.83 | Destabilizing | 0.1 | 1.81 | Ambiguous | 2.32 | Destabilizing | 1.39 | Destabilizing | 0.325 | Likely Benign | -2.90 | Deleterious | 0.995 | Probably Damaging | 0.970 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.1065 | 0.2856 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1362C>G | I454M 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I454M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools (SGM‑Consensus, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive results are FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for I454M. This conclusion is not contradicted by ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.312811 | Uncertain | 0.965 | 0.182 | 0.000 | -8.437 | Likely Pathogenic | 0.871 | Likely Pathogenic | Ambiguous | 1.06 | Ambiguous | 0.1 | 2.32 | Destabilizing | 1.69 | Ambiguous | 1.08 | Destabilizing | 0.292 | Likely Benign | -2.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.0566 | 0.2524 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.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.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.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.1391T>A | F464Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F464Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, while AlphaMissense‑Optimized and Foldetta provide uncertain results and are treated as unavailable evidence. Overall, the balance of evidence points to a pathogenic effect for F464Y, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.313424 | Uncertain | 0.961 | 0.178 | 0.000 | -10.056 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 1.35 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.80 | Ambiguous | 1.31 | Destabilizing | 0.387 | Likely Benign | -2.98 | Deleterious | 0.979 | Probably Damaging | 0.953 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.1081 | 0.1523 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.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.1403T>C | M468T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M468T is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database. Prediction tools that are available all converge on a pathogenic interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool reports a benign outcome. High‑accuracy assessments are consistent: AlphaMissense‑Optimized is “Uncertain,” SGM Consensus is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. **Based on the aggregate predictions, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” classification.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.284882 | Structured | 0.339253 | Uncertain | 0.932 | 0.257 | 0.000 | Uncertain | 2 | 6-33438435-T-C | 1 | 6.20e-7 | -12.399 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 3.47 | Destabilizing | 0.1 | 3.10 | Destabilizing | 3.29 | Destabilizing | 1.84 | Destabilizing | 0.801 | Likely Pathogenic | -3.85 | Deleterious | 0.994 | Probably Damaging | 0.985 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 3.37 | 31 | 0.2094 | 0.1950 | -1 | -1 | -2.6 | -30.09 | 214.6 | 47.1 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Pathogenic | The thioether group of Met468, located in the middle of an α helix (res. Ala461–Phe476), interacts with hydrophobic residues (e.g., Phe464, Leu465, Leu489) in an inter-helix space formed by two other α helices (res. Ala461–Phe476, res. Thr488–Gly502). In the variant simulations, the hydrophilic side chain of Thr468 does not pack favorably in the hydrophobic niche, and the methionine-aromatic stacking is lost. Although the hydroxyl group of Thr468 forms an H-bond with the backbone carbonyl group of Phe464, the integrity of the α helix is not affected in the simulations. No large-scale structural changes are observed during the variant simulations; however, due to the importance of hydrophobic packing, the effects could be more pronounced during protein folding. | |||||||||||||
| c.1412C>G | S471C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471C is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33438444‑C‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of predictions (10 benign vs. 3 pathogenic) indicate that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no reported pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | 6-33438444-C-G | 1 | 6.20e-7 | -3.454 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.0 | -0.05 | Likely Benign | 0.16 | Likely Benign | 0.07 | Likely Benign | 0.273 | Likely Benign | -2.90 | Deleterious | 0.000 | Benign | 0.001 | Benign | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.1048 | 0.4913 | -1 | 0 | 3.3 | 16.06 | |||||||||||||||||||||||||
| c.1414G>C | E472Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only Foldetta, which classifies the variant as benign. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive predictions come from FoldX, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact for E472Q, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -13.760 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 1.34 | Ambiguous | 0.3 | -0.67 | Ambiguous | 0.34 | Likely Benign | 0.89 | Ambiguous | 0.555 | Likely Pathogenic | -2.95 | Deleterious | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 2.39 | Pathogenic | 0.01 | Affected | 0.1388 | 0.5726 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1415A>C | E472A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E472A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all these methods uniformly classify the change as deleterious. Tools that are inconclusive or uncertain for this variant are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic outcome, the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, while Foldetta’s stability analysis remains uncertain. Taken together, the overwhelming majority of evidence points to a pathogenic effect for E472A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.359300 | Uncertain | 0.878 | 0.231 | 0.000 | -15.356 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | 1.81 | Ambiguous | 0.3 | 0.67 | Ambiguous | 1.24 | Ambiguous | 0.69 | Ambiguous | 0.732 | Likely Pathogenic | -5.90 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.32 | Pathogenic | 0.01 | Affected | 0.4639 | 0.6315 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1420G>T | D474Y 2D AIThe SynGAP1 missense variant D474Y is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, and premPS, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as benign. Overall, the preponderance of evidence points to a pathogenic effect for D474Y. This conclusion does not contradict ClinVar status, as the variant is currently unreported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -14.647 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.5 | -0.74 | Ambiguous | -0.24 | Likely Benign | 0.20 | Likely Benign | 0.864 | Likely Pathogenic | -7.72 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.30 | Pathogenic | 0.01 | Affected | 0.0493 | 0.4237 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1424G>A | R475Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R475Q is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438456‑G‑A). Prediction tools that indicate a benign effect include AlphaMissense‑Optimized, Foldetta, and Rosetta. Those that predict a pathogenic effect comprise SGM Consensus, SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Default; FoldX and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points toward a pathogenic impact, which contrasts with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.382696 | Uncertain | 0.852 | 0.261 | 0.000 | Uncertain | 2 | 6-33438456-G-A | 5 | 3.10e-6 | -12.087 | Likely Pathogenic | 0.721 | Likely Pathogenic | Likely Benign | 0.71 | Ambiguous | 0.1 | 0.12 | Likely Benign | 0.42 | Likely Benign | 0.82 | Ambiguous | 0.632 | Likely Pathogenic | -3.65 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.39 | 28 | 0.2190 | 0.1926 | 1 | 1 | 1.0 | -28.06 | 253.6 | 52.7 | 0.0 | 0.0 | -0.8 | 0.0 | X | X | X | Potentially Pathogenic | In the WT simulations, the guanidinium group of Arg475, located near the end of an α-helix (res. Ala461-Phe476), stacks with the phenyl ring of Phe476 and forms a salt bridge with Glu472. Additionally, Arg475 occasionally forms another salt bridge with the carboxylate group of Glu486 on the α-α loop connecting the two α-helices (res. Ala461-Phe476 and Leu489-Glu519) at the GAP-Ras interface. Therefore, Arg475 potentially plays a key role in positioning the loop by interacting with Glu486, which is necessary for the positioning of the “arginine finger” (Arg485) and, ultimately, for RasGTPase activation. In the variant simulations, Asn475 forms a hydrogen bond with Arg479 on the proceeding α-α loop. The absence of Phe476/Arg475 stacking and the Arg475-Glu472 salt bridge weakens the integrity of the terminal end of the α-helix during the variant simulations. Lastly, the potential effect of the residue swap on the SynGAP-Ras complex formation or GTPase activation cannot be fully addressed using the SynGAP solvent-only simulations. | |||||||||||
| c.1433A>T | E478V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E478V missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, Rosetta, polyPhen‑2 (HumDiv and HumVar), FATHMM, and premPS; pathogenic predictions from SGM‑Consensus, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: FoldX (uncertain) and AlphaMissense‑Optimized (uncertain). High‑accuracy assessments further split the signal: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. With six benign versus five pathogenic calls and no ClinVar evidence, the overall evidence slightly favors a benign interpretation, and there is no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.264545 | Structured | 0.414660 | Uncertain | 0.787 | 0.249 | 0.000 | -10.322 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.0 | 0.33 | Likely Benign | 0.44 | Likely Benign | 0.04 | Likely Benign | 0.385 | Likely Benign | -5.84 | Deleterious | 0.434 | Benign | 0.199 | Benign | 3.35 | Benign | 0.01 | Affected | 0.0586 | 0.6604 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1444C>T | L482F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from FoldX and premPS, while pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as Uncertain, SGM Consensus as Likely Pathogenic, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L482F. This conclusion is consistent with the absence of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -11.257 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.48 | Likely Benign | 0.0 | 1.09 | Ambiguous | 0.79 | Ambiguous | 0.43 | Likely Benign | 0.724 | Likely Pathogenic | -3.95 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | -1.22 | Pathogenic | 0.01 | Affected | 0.0457 | 0.1814 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1445T>C | L482P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482P is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Based on the unanimous computational evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -12.866 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 3.59 | Destabilizing | 0.1 | 10.87 | Destabilizing | 7.23 | Destabilizing | 1.55 | Destabilizing | 0.896 | Likely Pathogenic | -6.91 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.30 | Pathogenic | 0.01 | Affected | 0.2756 | 0.0825 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| c.1445T>G | L482R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L482R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate pathogenicity, while FoldX, Rosetta, and Foldetta return uncertain results. In a consensus framework, the SGM‑Consensus score is “Likely Pathogenic,” reflecting the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus is Likely Pathogenic, and Foldetta remains inconclusive. Taken together, the overwhelming majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.426236 | Uncertain | 0.795 | 0.248 | 0.000 | -14.684 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.74 | Ambiguous | 0.1 | 1.31 | Ambiguous | 1.03 | Ambiguous | 1.53 | Destabilizing | 0.878 | Likely Pathogenic | -5.92 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | -1.27 | Pathogenic | 0.01 | Affected | 0.1255 | 0.0679 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1459A>G | N487D 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N487D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include Rosetta, Foldetta, and FATHMM, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX and premPS are inconclusive. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, while Foldetta indicates a benign folding stability change. Overall, the preponderance of evidence points to a pathogenic effect for this variant, 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 | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.330 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.30 | Likely Benign | 0.84 | Ambiguous | 0.513 | Likely Pathogenic | -4.97 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.81 | Benign | 0.01 | Affected | 0.1728 | 0.1815 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| 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.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.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.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.1465C>G | L489V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, while only AlphaMissense‑Optimized predicts a benign outcome. Uncertain results are reported by Rosetta, Foldetta, 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 as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for L489V. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database record. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | -9.345 | Likely Pathogenic | 0.467 | Ambiguous | Likely Benign | 2.09 | Destabilizing | 0.0 | 1.70 | Ambiguous | 1.90 | Ambiguous | 1.25 | Destabilizing | 0.586 | Likely Pathogenic | -2.55 | Deleterious | 0.998 | Probably Damaging | 0.992 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.1665 | 0.4108 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.1465C>T | L489F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L489F is listed in ClinVar with an uncertain significance (ClinVar ID 522018.0) and is present in the gnomAD database (gnomAD ID 6‑33438497‑C‑T). In silico prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while no tool predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No prediction or folding‑stability result is missing or ambiguous. **Thus, the variant is most likely pathogenic based on the collective predictions, and this does not contradict the ClinVar uncertain status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.326126 | Uncertain | 0.949 | 0.234 | 0.125 | Uncertain | 2 | 6-33438497-C-T | 1 | 6.20e-7 | -12.066 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 1.72 | Ambiguous | 0.5 | 1.14 | Ambiguous | 1.43 | Ambiguous | 0.56 | Ambiguous | 0.724 | Likely Pathogenic | -3.76 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.51 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0791 | 0.3729 | 2 | 0 | -1.0 | 34.02 | 246.4 | -17.8 | 0.0 | 0.0 | 0.6 | 0.1 | X | Potentially Benign | The iso-butyl side chain of Leu489, located in the α-helix (res. Leu489-Glu519) within an inter-helix space of four helices (res. Ala461-Phe476, res. Val441-Ser457, and res. Met414-Glu436), packs with hydrophobic residues (e.g., Cys432, Ala448, Lys444, Ala493, Val447, Met468) in the inter-helix space. In the variant simulations, the phenyl ring of the Phe489 side chain can also pack favorably in the hydrophobic region. However, due to the size difference, the aromatic side chain of Phe489 tends to reposition to escape the tight region to accommodate the larger side chain, stacking with Lys444. Although no apparent negative changes are observed during the variant simulation, the size difference between the swapped residues could affect the protein folding process. | |||||||||||||
| c.1468G>C | A490P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Among the available in‑silico predictors, 10 tools (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) uniformly predict a pathogenic effect, whereas only Foldetta predicts a benign outcome; FoldX, Rosetta, and AlphaMissense‑Optimized are inconclusive. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) is benign. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | Uncertain | 1 | -12.905 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | -1.27 | Ambiguous | 0.1 | 1.31 | Ambiguous | 0.02 | Likely Benign | 1.07 | Destabilizing | 0.878 | Likely Pathogenic | -4.81 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1755 | 0.3071 | -1 | 1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.1469C>G | A490G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A490G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Pathogenic). Predictions that are uncertain or inconclusive are FoldX, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for A490G. 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 Pathogenic | GAP | 0.120615 | Structured | 0.322979 | Uncertain | 0.938 | 0.210 | 0.125 | -9.767 | Likely Pathogenic | 0.384 | Ambiguous | Likely Benign | 1.24 | Ambiguous | 0.0 | 2.00 | Destabilizing | 1.62 | Ambiguous | 1.13 | Destabilizing | 0.744 | Likely Pathogenic | -3.44 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.46 | Pathogenic | 0.01 | Affected | 0.2051 | 0.2228 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1471A>G | T491A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T491A is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33438503‑A‑G). Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta. Tools that predict a pathogenic effect include SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions (10 pathogenic vs. 3 benign) indicate a likely pathogenic impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | 6-33438503-A-G | 1 | 6.20e-7 | -11.033 | Likely Pathogenic | 0.934 | Likely Pathogenic | Ambiguous | 0.10 | Likely Benign | 0.3 | -0.27 | Likely Benign | -0.09 | Likely Benign | 1.06 | Destabilizing | 0.851 | Likely Pathogenic | -4.82 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3903 | 0.2874 | 0 | 1 | 2.5 | -30.03 | ||||||||||||||||||||||||
| c.1474A>G | K492E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K492E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. The remaining tools—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic or likely pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized scores it as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, which contradicts its current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.061840 | Structured | 0.327121 | Uncertain | 0.947 | 0.192 | 0.000 | Conflicting | 2 | -16.175 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 1.53 | Ambiguous | 0.1 | 1.90 | Ambiguous | 1.72 | Ambiguous | 1.42 | Destabilizing | 0.510 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.99 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2968 | 0.0650 | 1 | 0 | 0.4 | 0.94 | |||||||||||||||||||||||||
| c.1478C>A | A493D 2D AISynGAP1 missense variant A493D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. Consequently, the variant is most likely pathogenic, and this assessment is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.340081 | Uncertain | 0.966 | 0.182 | 0.000 | -16.834 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.45 | Destabilizing | 1.5 | 3.59 | Destabilizing | 4.02 | Destabilizing | 1.60 | Destabilizing | 0.925 | Likely Pathogenic | -5.25 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 0.1437 | 0.1541 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1481T>C | I494T 2D AIThe SynGAP1 missense variant I494T is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming majority of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.155435 | Structured | 0.353330 | Uncertain | 0.941 | 0.157 | 0.000 | -10.033 | Likely Pathogenic | 0.754 | Likely Pathogenic | Likely Benign | 2.45 | Destabilizing | 0.7 | 2.12 | Destabilizing | 2.29 | Destabilizing | 1.73 | Destabilizing | 0.907 | Likely Pathogenic | -4.61 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | -1.38 | Pathogenic | 0.01 | Affected | 0.1003 | 0.0640 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.1483G>A | E495K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E495K is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools with inconclusive results (Rosetta and premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also as pathogenic, while Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) indicates a benign effect. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect for E495K, which is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | Uncertain | 1 | -11.478 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.15 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.41 | Likely Benign | 0.70 | Ambiguous | 0.869 | Likely Pathogenic | -3.91 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1974 | 0.5039 | 1 | 0 | -0.4 | -0.94 | |||||||||||||||||||||||||
| c.1483G>C | E495Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495Q missense variant is not listed in ClinVar and has no reported allele in gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, and Foldetta, all of which score the substitution as benign. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta predicts benign stability. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -11.050 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | -0.27 | Likely Benign | 0.1 | 0.11 | Likely Benign | -0.08 | Likely Benign | 0.89 | Ambiguous | 0.748 | Likely Pathogenic | -2.92 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.42 | Pathogenic | 0.01 | Affected | 0.1093 | 0.4973 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1484A>C | E495A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E495A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include FoldX, while the remaining evaluated algorithms (REVEL, SIFT, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. No contradictory evidence is present from ClinVar or population databases. Overall, the preponderance of predictions supports a pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.364496 | Uncertain | 0.933 | 0.161 | 0.000 | -9.229 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 0.42 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.69 | Ambiguous | 0.834 | Likely Pathogenic | -5.84 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.38 | Pathogenic | 0.01 | Affected | 0.2711 | 0.4259 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1489T>A | Y497N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. Based on these concordant predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -11.884 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 3.64 | Destabilizing | 0.1 | 3.97 | Destabilizing | 3.81 | Destabilizing | 2.49 | Destabilizing | 0.870 | Likely Pathogenic | -8.85 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.66 | Pathogenic | 0.01 | Affected | 0.2114 | 0.0612 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.1489T>G | Y497D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y497D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a destabilizing, pathogenic effect. All available predictions are concordant and indicate a likely pathogenic impact. Thus, based on the collective computational evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.393608 | Uncertain | 0.950 | 0.181 | 0.000 | -12.128 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 4.70 | Destabilizing | 0.2 | 4.29 | Destabilizing | 4.50 | Destabilizing | 2.36 | Destabilizing | 0.918 | Likely Pathogenic | -9.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.67 | Pathogenic | 0.01 | Affected | 0.3621 | 0.0612 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.1495A>G | R499G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499G is listed in gnomAD (variant ID 6‑33438527‑A‑G) but has no ClinVar entry. Prediction tools that assess the variant’s effect on protein function overwhelmingly indicate a deleterious outcome: REVEL, FoldX‑MD (Rosetta component), Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as pathogenic. Only FoldX (overall) and AlphaMissense‑Optimized report uncertain results, which are treated as unavailable evidence. No tool predicts a benign effect. High‑accuracy assessments specifically show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as pathogenic. Taken together, the preponderance of evidence supports a pathogenic classification for R499G, and this conclusion is not contradicted by any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438527-A-G | 3 | 1.86e-6 | -9.960 | Likely Pathogenic | 0.789 | Likely Pathogenic | Ambiguous | 1.55 | Ambiguous | 0.1 | 2.75 | Destabilizing | 2.15 | Destabilizing | 1.41 | Destabilizing | 0.681 | Likely Pathogenic | -4.50 | Deleterious | 0.958 | Probably Damaging | 0.769 | Possibly Damaging | -1.47 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2888 | 0.1798 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1497A>C | R499S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499S is catalogued in gnomAD (ID 6‑33438529‑A‑C) but has no ClinVar entry. Functional prediction tools largely converge on a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate pathogenicity. No tool reports a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized and Foldetta are uncertain, whereas the SGM‑Consensus remains likely pathogenic. Protein‑stability predictions are inconclusive (FoldX uncertain, Rosetta pathogenic, Foldetta uncertain). Taken together, the overwhelming majority of evidence supports a pathogenic classification for R499S. This conclusion is consistent with the absence of a ClinVar status, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | 6-33438529-A-C | 1 | 6.20e-7 | -9.559 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.03 | Ambiguous | 0.0 | 2.19 | Destabilizing | 1.61 | Ambiguous | 1.40 | Destabilizing | 0.632 | Likely Pathogenic | -2.69 | Deleterious | 0.958 | Probably Damaging | 0.702 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2443 | 0.1649 | -1 | 0 | 3.7 | -69.11 | ||||||||||||||||||||||||
| c.1497A>T | R499S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R499S is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Rosetta all predict pathogenicity, while FoldX, AlphaMissense‑Optimized, and Foldetta are uncertain. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic, and Foldetta likewise yields an uncertain result. Taken together, the overwhelming majority of reliable tools predict a pathogenic effect, and there is no ClinVar annotation to contradict this assessment. Therefore, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.071867 | Structured | 0.386723 | Uncertain | 0.899 | 0.146 | 0.000 | -9.559 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.03 | Ambiguous | 0.0 | 2.19 | Destabilizing | 1.61 | Ambiguous | 1.40 | Destabilizing | 0.632 | Likely Pathogenic | -2.69 | Deleterious | 0.958 | Probably Damaging | 0.702 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2443 | 0.1649 | -1 | 0 | 3.7 | -69.11 | |||||||||||||||||||||||||||
| c.1498C>A | L500M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The premPS score is uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it yields a 2‑to‑2 split. No other high‑accuracy predictions are available. Overall, the majority of high‑accuracy tools lean toward a benign interpretation, and this assessment does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -9.945 | Likely Pathogenic | 0.301 | Likely Benign | Likely Benign | 0.15 | Likely Benign | 0.0 | -0.09 | Likely Benign | 0.03 | Likely Benign | 0.92 | Ambiguous | 0.590 | Likely Pathogenic | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0710 | 0.2202 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1499T>C | L500P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500P is listed in ClinVar (ID 2708686.0) as Pathogenic and is not reported in gnomAD. All available in‑silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Thus, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | Pathogenic | 1 | -15.898 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 5.91 | Destabilizing | 0.3 | 8.90 | Destabilizing | 7.41 | Destabilizing | 1.92 | Destabilizing | 0.894 | Likely Pathogenic | -6.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3103 | 0.0625 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||
| 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.1503T>G | I501M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I501M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions that are inconclusive or unavailable are FoldX, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign impact for I501M. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.079919 | Structured | 0.366596 | Uncertain | 0.886 | 0.153 | 0.000 | -7.452 | In-Between | 0.259 | Likely Benign | Likely Benign | 1.32 | Ambiguous | 0.2 | -0.19 | Likely Benign | 0.57 | Ambiguous | 0.95 | Ambiguous | 0.294 | Likely Benign | -2.32 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 0.0680 | 0.1589 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.1504G>A | G502S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G502S is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts a benign outcome, whereas the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -11.357 | Likely Pathogenic | 0.616 | Likely Pathogenic | Likely Benign | 2.09 | Destabilizing | 0.6 | 0.71 | Ambiguous | 1.40 | Ambiguous | 0.96 | Ambiguous | 0.839 | Likely Pathogenic | -5.74 | Deleterious | 0.975 | Probably Damaging | 0.862 | Possibly Damaging | -1.64 | Pathogenic | 0.01 | Affected | 0.2429 | 0.3217 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.1509G>C | Q503H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are therefore considered unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta remains uncertain. Overall, the majority of evaluated predictors (7 benign vs. 3 pathogenic) lean toward a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -5.335 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.2 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.48 | Likely Benign | 0.331 | Likely Benign | -3.40 | Deleterious | 0.002 | Benign | 0.004 | Benign | -1.52 | Pathogenic | 0.01 | Affected | 0.1091 | 0.2125 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1509G>T | Q503H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q503H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are PROVEAN, SIFT, and FATHMM. FoldX, Rosetta, and Foldetta report uncertain or inconclusive stability changes and are therefore considered unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta remains uncertain. Overall, the majority of evaluated predictors (7 benign vs. 3 pathogenic) lean toward a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.322935 | Uncertain | 0.848 | 0.168 | 0.000 | -5.335 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.94 | Ambiguous | 0.2 | 0.88 | Ambiguous | 0.91 | Ambiguous | 0.48 | Likely Benign | 0.331 | Likely Benign | -3.40 | Deleterious | 0.002 | Benign | 0.004 | Benign | -1.52 | Pathogenic | 0.01 | Affected | 0.1091 | 0.2125 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||
| c.1516C>A | L506I 2D AIThe SynGAP1 missense variant L506I is not reported in ClinVar and is absent from gnomAD. Consensus from standard in‑silico predictors shows a split: benign calls come from REVEL, PROVEAN, and AlphaMissense‑Optimized, whereas pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Default. High‑accuracy assessments give a pathogenic verdict from Foldetta (a combined FoldX‑MD/Rosetta stability analysis) and from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). AlphaMissense‑Optimized, however, predicts benign. Overall, the majority of reliable tools and the high‑accuracy methods favor a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.034884 | Structured | 0.279180 | Uncertain | 0.924 | 0.196 | 0.000 | -10.386 | Likely Pathogenic | 0.501 | Ambiguous | Likely Benign | 1.73 | Ambiguous | 1.0 | 2.85 | Destabilizing | 2.29 | Destabilizing | 0.98 | Ambiguous | 0.365 | Likely Benign | -1.99 | Neutral | 0.998 | Probably Damaging | 0.997 | Probably Damaging | 1.65 | Pathogenic | 0.01 | Affected | 0.0745 | 0.2033 | 2 | 2 | 0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.1516C>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.1522G>T | D508Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508Y missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labeling it likely pathogenic, and Foldetta predicting a benign outcome. Overall, the majority of evidence (seven pathogenic vs. five benign) points to a pathogenic impact. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -12.917 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | -0.53 | Ambiguous | 0.2 | 0.72 | Ambiguous | 0.10 | Likely Benign | 0.06 | Likely Benign | 0.363 | Likely Benign | -8.37 | Deleterious | 1.000 | Probably Damaging | 0.965 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0908 | 0.4736 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1525G>C | A509P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity are unanimous: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. No tool in the dataset predicts a benign effect, so the benign‑prediction group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic effect; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a pathogenic impact. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status (no report). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -13.234 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 5.82 | Destabilizing | 0.6 | 7.70 | Destabilizing | 6.76 | Destabilizing | 1.13 | Destabilizing | 0.884 | Likely Pathogenic | -4.15 | Deleterious | 0.987 | Probably Damaging | 0.844 | Possibly Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.1940 | 0.4570 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1525G>T | A509S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A509S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Four tools give uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS). High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie and thus inconclusive, and Foldetta is also inconclusive. Overall, the majority of standard predictors lean toward pathogenicity, while the most reliable single‑tool prediction (AlphaMissense‑Optimized) suggests benign. Given the balance of evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.025762 | Structured | 0.250110 | Uncertain | 0.923 | 0.256 | 0.000 | -9.997 | Likely Pathogenic | 0.171 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.23 | Ambiguous | 0.59 | Ambiguous | 0.621 | Likely Pathogenic | -2.18 | Neutral | 0.119 | Benign | 0.468 | Possibly Damaging | -1.35 | Pathogenic | 0.01 | Affected | 0.2410 | 0.4384 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1528A>T | I510F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I510F is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS and AlphaMissense‑Optimized, whereas the majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and Foldetta) predict a pathogenic impact; Rosetta remains uncertain. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.025762 | Structured | 0.250630 | Uncertain | 0.945 | 0.273 | 0.000 | -8.185 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 4.66 | Destabilizing | 0.7 | 1.38 | Ambiguous | 3.02 | Destabilizing | 0.50 | Likely Benign | 0.692 | Likely Pathogenic | -2.64 | Deleterious | 0.991 | Probably Damaging | 0.854 | Possibly Damaging | -1.14 | Pathogenic | 0.01 | Affected | 0.0552 | 0.1794 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1532G>T | G511V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511V is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no classification for G511V. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -11.738 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 3.47 | Destabilizing | 0.2 | 0.79 | Ambiguous | 2.13 | Destabilizing | 0.65 | Ambiguous | 0.540 | Likely Pathogenic | -8.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.16 | Benign | 0.01 | Affected | 0.1557 | 0.3019 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.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.1543C>T | R515C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R515C is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438786‑C‑T). Prediction tools that indicate a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN)—classify the variant as 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 high‑accuracy tools provide a definitive prediction. Based on the overall consensus, the variant is most likely pathogenic, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | Uncertain | 1 | 6-33438786-C-T | 1 | 6.20e-7 | -10.973 | Likely Pathogenic | 0.628 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.0 | 1.13 | Ambiguous | 1.07 | Ambiguous | 0.72 | Ambiguous | 0.691 | Likely Pathogenic | -5.49 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3055 | 0.1546 | -3 | -4 | 7.0 | -53.05 | ||||||||||||||||||||||
| c.1544G>A | R515H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R515H is listed in ClinVar with an uncertain significance (ClinVar ID 638438.0) and is present in gnomAD (variant ID 6‑33438787‑G‑A). Prediction tools that agree on a benign effect include AlphaMissense‑Default and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus remains pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive. Overall, the balance of evidence favors a pathogenic effect, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.191256 | Uncertain | 0.924 | 0.275 | 0.000 | Uncertain | 1 | 6-33438787-G-A | 3 | 1.86e-6 | -10.774 | Likely Pathogenic | 0.337 | Likely Benign | Likely Benign | 1.07 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.91 | Ambiguous | 1.09 | Destabilizing | 0.730 | Likely Pathogenic | -3.44 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.2343 | 0.0746 | 2 | 0 | 1.3 | -19.05 | 239.2 | 77.8 | 0.0 | 0.0 | 0.4 | 0.2 | X | Potentially Benign | The guanidinium group of Arg515, located in the middle of an α-helix at the GAP domain (res. Gly502-Tyr518), forms salt bridges with the carboxylate groups of Glu512 on the same helix and Glu217 on a loop in the PH domain. Additionally, the positively charged Arg515 side chain forms hydrogen bonds with Leu610 and Gln612 in an opposing loop (res. Gly609-Asp616). In contrast, in the variant simulations, the imidazole ring of His515 cannot form salt bridges with either of the acidic residues, and its side chain is too short to form hydrogen bonds with the loop residues. Accordingly, the residue swap could weaken the tertiary structure assembly of the protein. Due to the missing N-terminal part of the SynGAP model, the effect could be largely underestimated or missing. Notably, the doubly protonated and positively charged form of histidine was not simulated here. | |||||||||||||
| c.1549C>A | L517M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. Benign predictions are provided by FoldX and PROVEAN. High‑accuracy assessments are mixed: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, whereas AlphaMissense‑Optimized and Foldetta yield uncertain results and are treated as unavailable. No evidence from ClinVar contradicts these findings. Overall, the preponderance of evidence supports a pathogenic classification for L517M, with no conflict from existing database annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -11.613 | Likely Pathogenic | 0.799 | Likely Pathogenic | Ambiguous | 0.38 | Likely Benign | 0.2 | 1.22 | Ambiguous | 0.80 | Ambiguous | 0.93 | Ambiguous | 0.665 | Likely Pathogenic | -1.74 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.0775 | 0.2558 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.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.1558T>C | S520P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while premPS remains inconclusive. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Overall, the evidence strongly supports a pathogenic impact for S520P, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.707 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.72 | Destabilizing | 0.8 | 8.86 | Destabilizing | 6.29 | Destabilizing | 0.83 | Ambiguous | 0.855 | Likely Pathogenic | -4.57 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.2154 | 0.4776 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.1558T>G | S520A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S520A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized, whereas a larger group—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. The premPS score is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy consensus is split, but the pathogenic predictions dominate. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.417 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 0.03 | Likely Benign | 0.2 | 0.19 | Likely Benign | 0.11 | Likely Benign | 0.56 | Ambiguous | 0.523 | Likely Pathogenic | -2.55 | Deleterious | 0.944 | Possibly Damaging | 0.987 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.4887 | 0.3636 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.1565A>G | E522G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522G missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as deleterious. No tool reports a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a damaging effect, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX, Rosetta, and premPS are uncertain and are treated as unavailable evidence. Overall, the computational evidence overwhelmingly 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 | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -10.053 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.0 | 1.62 | Ambiguous | 1.17 | Ambiguous | 0.58 | Ambiguous | 0.823 | Likely Pathogenic | -6.59 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.2672 | 0.3654 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1565A>T | E522V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E522V 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 FoldX, Rosetta, Foldetta, and premPS, whereas the remaining tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.092881 | Structured | 0.046216 | Uncertain | 0.823 | 0.376 | 0.000 | -11.985 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.09 | Likely Benign | 0.2 | 0.00 | Likely Benign | 0.05 | Likely Benign | 0.18 | Likely Benign | 0.751 | Likely Pathogenic | -6.59 | Deleterious | 0.995 | Probably Damaging | 0.996 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.0537 | 0.4514 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1579G>A | D527N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527N missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, and premPS, whereas a majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. The high‑accuracy consensus methods give mixed results: AlphaMissense‑Optimized is uncertain, SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign outcome. Overall, the preponderance of evidence points toward a pathogenic effect, 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 | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -12.645 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.31 | Likely Benign | 1.0 | 0.09 | Likely Benign | 0.20 | Likely Benign | 0.22 | Likely Benign | 0.730 | Likely Pathogenic | -4.87 | Deleterious | 0.992 | Probably Damaging | 0.990 | Probably Damaging | -2.13 | Pathogenic | 0.01 | Affected | 0.0910 | 0.3754 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1580A>G | D527G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D527G 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 prediction comes from premPS, while all other evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta—indicate pathogenicity. FoldX is uncertain and therefore not counted as evidence for either side. High‑accuracy methods reinforce the pathogenic assessment: 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. No contradictory evidence exists in ClinVar. **Thus, the variant is most likely pathogenic based on the collective predictions, with no ClinVar status to contradict this assessment.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -15.177 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.71 | Ambiguous | 1.0 | 4.22 | Destabilizing | 2.97 | Destabilizing | 0.33 | Likely Benign | 0.933 | Likely Pathogenic | -6.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -2.39 | Pathogenic | 0.01 | Affected | 0.2847 | 0.4366 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.1582C>G | P528A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized, while the remaining pathogenic‑predicting tools are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, Foldetta, premPS) are uncertain. High‑accuracy methods give AlphaMissense‑Optimized a benign score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) a pathogenic prediction, and Foldetta an uncertain result. Overall, the majority of evidence points to a pathogenic effect. Thus, the variant is most likely pathogenic, and this assessment is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.562 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 1.57 | Ambiguous | 0.1 | 1.49 | Ambiguous | 1.53 | Ambiguous | 0.69 | Ambiguous | 0.548 | Likely Pathogenic | -7.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 0.3146 | 0.3914 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1582C>T | P528S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528S missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Only FATHMM predicts a benign outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. No folding‑stability metrics (FoldX, Rosetta, premPS) provide definitive evidence. Overall, the preponderance of pathogenic predictions suggests 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 | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -11.729 | Likely Pathogenic | 0.819 | Likely Pathogenic | Ambiguous | 1.88 | Ambiguous | 0.1 | 1.28 | Ambiguous | 1.58 | Ambiguous | 0.80 | Ambiguous | 0.617 | Likely Pathogenic | -7.65 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 0.3115 | 0.3982 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1583C>G | P528R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P528R missense variant is not reported in ClinVar and is absent from gnomAD. No in silico predictor classifies it as benign; the following tools predict pathogenicity: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Predictions that are uncertain or inconclusive (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of 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 | 0.225814 | Structured | 0.020396 | Uncertain | 0.909 | 0.403 | 0.000 | -16.367 | Likely Pathogenic | 0.952 | Likely Pathogenic | Ambiguous | 0.76 | Ambiguous | 0.4 | 0.67 | Ambiguous | 0.72 | Ambiguous | 0.73 | Ambiguous | 0.615 | Likely Pathogenic | -8.58 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1261 | 0.2543 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1588A>C | K530Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K530Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain. 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 (13/16) predict pathogenicity, whereas only three predict benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.018455 | Uncertain | 0.891 | 0.409 | 0.000 | -10.593 | Likely Pathogenic | 0.574 | Likely Pathogenic | Likely Benign | 0.31 | Likely Benign | 0.0 | 0.87 | Ambiguous | 0.59 | Ambiguous | 0.13 | Likely Benign | 0.524 | Likely Pathogenic | -3.18 | Deleterious | 0.698 | Possibly Damaging | 0.694 | Possibly Damaging | -1.61 | Pathogenic | 0.01 | Affected | 0.3001 | 0.0941 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.1591T>A | C531S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531S is not reported in ClinVar and has no entries in gnomAD. Prediction tools that assess pathogenicity largely agree on a deleterious effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. In contrast, only three tools predict a benign outcome: FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy methods provide a mixed picture: AlphaMissense‑Optimized reports a benign effect, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta also predicts benign stability. Overall, the preponderance of evidence points to a pathogenic impact for C531S. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -8.213 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.02 | Likely Benign | 0.0 | 0.77 | Ambiguous | 0.38 | Likely Benign | 1.23 | Destabilizing | 0.519 | Likely Pathogenic | -8.00 | Deleterious | 0.958 | Probably Damaging | 0.533 | Possibly Damaging | -1.18 | Pathogenic | 0.01 | Affected | 0.3716 | 0.1782 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1592G>C | C531S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and AlphaMissense‑Optimized, whereas pathogenic predictions are made by SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; Rosetta remains uncertain. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized indicates benign, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic, and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the preponderance of evidence points to a pathogenic effect for C531S, 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 | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -8.213 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.02 | Likely Benign | 0.0 | 0.77 | Ambiguous | 0.38 | Likely Benign | 1.23 | Destabilizing | 0.508 | Likely Pathogenic | -8.00 | Deleterious | 0.958 | Probably Damaging | 0.533 | Possibly Damaging | -1.18 | Pathogenic | 0.01 | Affected | 0.3716 | 0.1782 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.1592G>T | C531F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C531F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Rosetta and polyPhen‑2 HumVar, while the majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive or uncertain results are AlphaMissense‑Optimized, Foldetta, and premPS. High‑accuracy assessments show SGM‑Consensus as “Likely Pathogenic”; AlphaMissense‑Optimized is uncertain; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also uncertain. Taken together, the preponderance of evidence from multiple pathogenic‑predicting algorithms and the SGM‑Consensus score indicates that the variant is most likely pathogenic. 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 | 0.281712 | Structured | 0.017941 | Uncertain | 0.878 | 0.401 | 0.000 | -10.428 | Likely Pathogenic | 0.842 | Likely Pathogenic | Ambiguous | 2.47 | Destabilizing | 1.6 | 0.26 | Likely Benign | 1.37 | Ambiguous | 0.59 | Ambiguous | 0.519 | Likely Pathogenic | -8.89 | Deleterious | 0.866 | Possibly Damaging | 0.244 | Benign | -1.23 | Pathogenic | 0.01 | Affected | 0.1103 | 0.3784 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.1606T>A | L536M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L536M missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining tools—Rosetta, Foldetta, 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 as uncertain. Overall, the majority of evidence points toward a pathogenic impact, 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. | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.124 | Likely Pathogenic | 0.462 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.1 | 1.18 | Ambiguous | 0.78 | Ambiguous | 0.93 | Ambiguous | 0.571 | Likely Pathogenic | -1.94 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.0937 | 0.3299 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1608G>C | L536F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. Predictions that are uncertain or inconclusive are FoldX, 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 (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.316 | Likely Pathogenic | 0.851 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.5 | 0.40 | Likely Benign | 0.86 | Ambiguous | 0.70 | Ambiguous | 0.724 | Likely Pathogenic | -3.90 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0874 | 0.2804 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1608G>T | L536F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L536F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only Rosetta. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. Predictions that are uncertain or inconclusive are FoldX, 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 (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.042188 | Uncertain | 0.931 | 0.341 | 0.000 | -10.316 | Likely Pathogenic | 0.851 | Likely Pathogenic | Ambiguous | 1.31 | Ambiguous | 0.5 | 0.40 | Likely Benign | 0.86 | Ambiguous | 0.70 | Ambiguous | 0.722 | Likely Pathogenic | -3.90 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.36 | Pathogenic | 0.01 | Affected | 0.0874 | 0.2804 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1615C>T | H539Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539Y has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include only premPS, whereas the remaining evaluated algorithms (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default) all predict a pathogenic impact. Predictions marked as uncertain are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports pathogenicity, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for H539Y. This conclusion is not contradicted by ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -13.177 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | -1.22 | Ambiguous | 0.0 | -1.12 | Ambiguous | -1.17 | Ambiguous | 0.34 | Likely Benign | 0.906 | Likely Pathogenic | -5.60 | Deleterious | 0.998 | Probably Damaging | 0.990 | Probably Damaging | -1.26 | Pathogenic | 0.01 | Affected | 0.0776 | 0.2552 | 0 | 2 | 1.9 | 26.03 | |||||||||||||||||||||||||||||
| c.1616A>C | H539P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H539P missense variant 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 FoldX, whereas all other evaluated algorithms—REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Taken together, the overwhelming majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -15.182 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | 9.08 | Destabilizing | 4.65 | Destabilizing | 1.03 | Destabilizing | 0.913 | Likely Pathogenic | -9.18 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.1900 | 0.2794 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.1616A>T | H539L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H539L is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include Rosetta and premPS, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta’s stability prediction is uncertain. No evidence from the available data contradicts the ClinVar status, which is currently unreported. Overall, the preponderance of computational evidence indicates that H539L is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.060549 | Structured | 0.031398 | Uncertain | 0.948 | 0.360 | 0.000 | -14.161 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | -1.76 | Ambiguous | 0.1 | -0.17 | Likely Benign | -0.97 | Ambiguous | 0.35 | Likely Benign | 0.879 | Likely Pathogenic | -10.17 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.0758 | 0.3680 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.1619A>C | Q540P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q540P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic, while premPS is uncertain. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a pathogenic effect. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, 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 | 0.085092 | Structured | 0.029522 | Uncertain | 0.958 | 0.371 | 0.000 | -16.096 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.95 | Destabilizing | 0.3 | 10.06 | Destabilizing | 7.01 | Destabilizing | 0.73 | Ambiguous | 0.922 | Likely Pathogenic | -5.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.1882 | 0.3654 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1627C>A | L543M 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L543M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and PROVEAN, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Rosetta. Predictions that are uncertain (FoldX, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments give AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of available tools predict a deleterious effect, indicating that the variant is most likely pathogenic. 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 | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -11.452 | Likely Pathogenic | 0.922 | Likely Pathogenic | Ambiguous | 0.68 | Ambiguous | 0.2 | 2.53 | Destabilizing | 1.61 | Ambiguous | 0.99 | Ambiguous | 0.382 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.93 | Pathogenic | 0.01 | Affected | 0.0788 | 0.2172 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| 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.1641T>G | C547W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C547W is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Taken together, the overwhelming consensus from both general and high‑accuracy predictors is that C547W 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 | 0.045352 | Structured | 0.007912 | Uncertain | 0.971 | 0.275 | 0.000 | -15.788 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 11.03 | Destabilizing | 0.3 | 2.63 | Destabilizing | 6.83 | Destabilizing | 0.54 | Ambiguous | 0.764 | Likely Pathogenic | -10.64 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.1854 | 0.2750 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.1649C>A | A550D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A550D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect. Benign predictions: none. Pathogenic predictions: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized. Uncertain predictions: Rosetta and Foldetta. High‑accuracy assessments further support a damaging outcome: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the overwhelming majority of evidence indicates a pathogenic effect. Based on the aggregate predictions, the variant is most likely pathogenic, and this is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -18.844 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.51 | Destabilizing | 0.1 | 1.46 | Ambiguous | 1.99 | Ambiguous | 1.01 | Destabilizing | 0.879 | Likely Pathogenic | -5.43 | Deleterious | 0.999 | Probably Damaging | 0.971 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.1333 | 0.1783 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.1649C>G | A550G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A550G missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, Foldetta, and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. Overall, the majority of reliable predictors indicate a pathogenic 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 Pathogenic | GAP | 0.018106 | Structured | 0.007241 | Uncertain | 0.954 | 0.265 | 0.000 | -15.086 | Likely Pathogenic | 0.776 | Likely Pathogenic | Likely Benign | 1.73 | Ambiguous | 0.0 | 1.82 | Ambiguous | 1.78 | Ambiguous | 0.85 | Ambiguous | 0.769 | Likely Pathogenic | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.932 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.1595 | 0.2758 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.1652T>A | L551Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551Q is not reported in ClinVar and is present in gnomAD (allele ID 6‑33438895‑T‑A). In silico prediction tools uniformly indicate a deleterious effect: benign‑predicting tools: none; pathogenic‑predicting tools: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are inconclusive or missing. **Thus, the variant is most likely pathogenic based on the available predictions, and this conclusion does not contradict the ClinVar status (no entry).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | 6-33438895-T-A | 1 | 6.20e-7 | -13.632 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.48 | Destabilizing | 0.1 | 2.19 | Destabilizing | 2.34 | Destabilizing | 2.37 | Destabilizing | 0.936 | Likely Pathogenic | -3.68 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0983 | 0.0688 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||
| c.1652T>C | L551P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551P (ClinVar ID 547942.0) is classified as Pathogenic in ClinVar and is not reported in gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. No tool in the dataset predicts a benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized is Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, is Pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | Likely Pathogenic | 1 | -14.620 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.66 | Destabilizing | 0.1 | 6.58 | Destabilizing | 6.62 | Destabilizing | 2.66 | Destabilizing | 0.953 | Likely Pathogenic | -4.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3377 | 0.1353 | -3 | -3 | -5.4 | -16.04 | 208.6 | 60.9 | 0.1 | 0.0 | -0.3 | 0.0 | X | Potentially Pathogenic | L551 is located on an α-helix (res. Ala533-Val560). The iso-butyl side chain of Leu551 hydrophobically packs with nearby hydrophobic residues such as Cys547, Phe652, Leu633, and Ile630 in the inter-helix space. In the variant simulations, the pyrrolidine side chain of Pro551 is not as optimal as leucine for hydrophobic packing with the nearby residues. Moreover, Pro551 lacks the amide group, and thus, it cannot form a hydrogen bond with the backbone carbonyl group of Cys547, which disrupts the continuity of the secondary structure element. | ||||||||||||||||
| c.1652T>G | L551R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the only tool with an uncertain outcome is FoldX. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Based on the concordant predictions from multiple independent algorithms and the absence of benign 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 | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | -15.420 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.81 | Ambiguous | 0.2 | 2.35 | Destabilizing | 2.08 | Destabilizing | 2.09 | Destabilizing | 0.949 | Likely Pathogenic | -3.85 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 0.1278 | 0.0530 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1658A>T | K553M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K553M is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and premPS, whereas the majority of tools predict it to be pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.006539 | Uncertain | 0.949 | 0.246 | 0.000 | -16.086 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | -0.08 | Likely Benign | 0.0 | -0.06 | Likely Benign | -0.07 | Likely Benign | 0.32 | Likely Benign | 0.854 | Likely Pathogenic | -5.76 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.0921 | 0.2756 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1664T>C | V555A 2D 3DClick to see structure in 3D Viewer AISynGAP1 V555A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly indicate a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all classify the variant as pathogenic. No tool predicts a benign outcome. Predictions that are inconclusive—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—are listed as uncertain and do not alter the overall assessment. High‑accuracy methods give a pathogenic consensus from SGM and an uncertain result from AlphaMissense‑Optimized and Foldetta. Consequently, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -8.781 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.91 | Ambiguous | 0.0 | 0.90 | Ambiguous | 0.91 | Ambiguous | 1.04 | Destabilizing | 0.633 | Likely Pathogenic | -3.48 | Deleterious | 0.979 | Probably Damaging | 0.956 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.2602 | 0.1761 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.1664T>G | V555G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V555G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default; no tool predicts it benign. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as pathogenic. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -13.327 | Likely Pathogenic | 0.899 | Likely Pathogenic | Ambiguous | 2.07 | Destabilizing | 0.1 | 2.22 | Destabilizing | 2.15 | Destabilizing | 1.07 | Destabilizing | 0.798 | Likely Pathogenic | -6.35 | Deleterious | 0.984 | Probably Damaging | 1.000 | Probably Damaging | -1.39 | Pathogenic | 0.01 | Affected | 0.1994 | 0.1677 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.1666A>T | N556Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized, whereas tools that predict a pathogenic impact are REVEL, 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, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus as pathogenic. Taken together, the majority of evidence (8 pathogenic vs 5 benign) points to a pathogenic effect, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -12.533 | Likely Pathogenic | 0.730 | Likely Pathogenic | Likely Benign | -0.01 | Likely Benign | 0.1 | -0.40 | Likely Benign | -0.21 | Likely Benign | 0.28 | Likely Benign | 0.743 | Likely Pathogenic | -6.69 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.40 | Pathogenic | 0.01 | Affected | 0.0690 | 0.3157 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.1669T>C | S557P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -15.383 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.91 | Destabilizing | 0.4 | 8.79 | Destabilizing | 7.85 | Destabilizing | 1.09 | Destabilizing | 0.934 | Likely Pathogenic | -4.60 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.76 | Pathogenic | 0.01 | Affected | 0.2222 | 0.6239 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1682T>A | F561Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F561Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a deleterious effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a benign outcome; the remaining predictions (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) are uncertain or unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Based on the consensus of the majority of evidence‑based predictors, 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 | 0.024826 | Structured | 0.018013 | Uncertain | 0.903 | 0.196 | 0.000 | -12.692 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 1.54 | Ambiguous | 0.1 | 0.75 | Ambiguous | 1.15 | Ambiguous | 1.28 | Destabilizing | 0.693 | Likely Pathogenic | -2.99 | Deleterious | 0.988 | Probably Damaging | 0.976 | Probably Damaging | -1.34 | Pathogenic | 0.01 | Affected | 0.1344 | 0.1120 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.1684C>G | P562A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P562A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: only premPS classifies it as benign, whereas REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity; Rosetta remains uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports a pathogenic change, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenicity. Consequently, the variant is most likely pathogenic. This assessment does not contradict ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022306 | Structured | 0.023606 | Uncertain | 0.893 | 0.200 | 0.000 | -13.554 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.87 | Destabilizing | 0.0 | 1.28 | Ambiguous | 2.08 | Destabilizing | 0.39 | Likely Benign | 0.633 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.59 | Pathogenic | 0.01 | Affected | 0.3418 | 0.2883 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.1684C>T | P562S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P562S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity. The only tools with uncertain outcomes are Rosetta and premPS, which provide inconclusive results. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.022306 | Structured | 0.023606 | Uncertain | 0.893 | 0.200 | 0.000 | -14.293 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 2.93 | Destabilizing | 0.1 | 1.59 | Ambiguous | 2.26 | Destabilizing | 0.70 | Ambiguous | 0.708 | Likely Pathogenic | -7.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 0.62 | Pathogenic | 0.01 | Affected | 0.3365 | 0.2900 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1687A>T | R563W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R563W is not 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. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. No evidence from the uncertain tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) supports either outcome. Overall, the balance of evidence favors a pathogenic classification for R563W, 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 | 0.039760 | Structured | 0.031987 | Uncertain | 0.876 | 0.209 | 0.000 | -12.454 | Likely Pathogenic | 0.854 | Likely Pathogenic | Ambiguous | 1.25 | Ambiguous | 0.1 | 0.79 | Ambiguous | 1.02 | Ambiguous | 0.34 | Likely Benign | 0.302 | Likely Benign | -6.75 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.42 | Benign | 0.01 | Affected | 0.1378 | 0.2088 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||
| c.1697A>T | K566M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K566M is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign are Foldetta and premPS, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict it to be pathogenic; FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.027463 | Structured | 0.047887 | Uncertain | 0.924 | 0.219 | 0.000 | -13.208 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.2 | -0.51 | Ambiguous | 0.15 | Likely Benign | 0.37 | Likely Benign | 0.804 | Likely Pathogenic | -5.51 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.0936 | 0.3826 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1705T>A | F569I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F569I is not listed in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as pathogenic. No predictor reports a benign outcome, so the benign group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates pathogenicity. Consequently, the variant is most likely pathogenic, and this prediction 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 | 0.024393 | Structured | 0.054289 | Uncertain | 0.941 | 0.242 | 0.000 | -15.362 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.75 | Destabilizing | 0.2 | 4.23 | Destabilizing | 3.99 | Destabilizing | 1.51 | Destabilizing | 0.903 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.31 | Pathogenic | 0.01 | Affected | 0.1950 | 0.1973 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1715G>C | W572S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W572S is listed in ClinVar as Pathogenic (ClinVar ID 1069317.0) and is not reported in gnomAD. All available in silico predictors classify the variant as pathogenic: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Therefore, the variant is most likely pathogenic, and this prediction aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.150080 | Structured | 0.039626 | Uncertain | 0.935 | 0.256 | 0.000 | Pathogenic | 1 | -17.461 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.78 | Destabilizing | 0.2 | 3.37 | Destabilizing | 4.58 | Destabilizing | 1.79 | Destabilizing | 0.775 | Likely Pathogenic | -12.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.3958 | 0.0857 | -2 | -3 | 0.1 | -99.14 | 235.1 | 76.6 | 0.0 | 0.0 | -0.4 | 0.1 | X | Potentially Pathogenic | The introduced residue Ser572, located in an α-helix (res. Arg563-Glu578), is considerably smaller than the tryptophan it replaced. The indole ring of the Trp572 side chain lies in a hydrophobic inter-helix space, where it makes extensive hydrophobic interactions with nearby residues such as Met470, Phe569, Leu588, and Ile589. In the variant simulations, all these favorable packing interactions are completely removed, as the introduced residue Ser572 is too hydrophilic or small to fill the hydrophobic niche occupied by the indole ring. Moreover, the hydroxyl group of Ser572 forms hydrogen bonds with the carbonyl groups of Glu567 and Val568 within the same α-helix, potentially lowering its integrity. Overall, the residue swap is highly likely to cause critical protein folding problems that are underestimated based on the effects seen in the variant simulations. | ||||||||||||||||
| c.1717C>G | R573G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R573G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while no tool predicts a benign outcome. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar annotation exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.032433 | Uncertain | 0.934 | 0.235 | 0.000 | -15.387 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.71 | Destabilizing | 0.7 | 3.16 | Destabilizing | 3.44 | Destabilizing | 1.37 | Destabilizing | 0.744 | Likely Pathogenic | -6.01 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.45 | Pathogenic | 0.01 | Affected | 0.2931 | 0.2166 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.1718G>C | R573P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R573P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a pathogenic impact. Based on the uniform predictions, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.032433 | Uncertain | 0.934 | 0.235 | 0.000 | -16.684 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 5.76 | Destabilizing | 1.1 | 8.58 | Destabilizing | 7.17 | Destabilizing | 1.21 | Destabilizing | 0.831 | Likely Pathogenic | -5.78 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.1961 | 0.3239 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1718G>T | R573L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R573L is listed in ClinVar as Pathogenic (ClinVar ID 521291.0) and is not reported in gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly indicate a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool in the dataset predicts a benign outcome. Predictions that rely on protein‑folding stability (FoldX, Rosetta, Foldetta, premPS) are inconclusive and are therefore treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports pathogenic; Foldetta remains uncertain. Based on the collective evidence, the variant is most likely pathogenic, which is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.134866 | Structured | 0.032433 | Uncertain | 0.934 | 0.235 | 0.000 | Likely Pathogenic | 1 | -13.120 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.30 | Ambiguous | 0.6 | 1.11 | Ambiguous | 1.21 | Ambiguous | 0.80 | Ambiguous | 0.833 | Likely Pathogenic | -5.74 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1503 | 0.3083 | -3 | -2 | 8.3 | -43.03 | 237.4 | 60.7 | 0.0 | 0.0 | -0.7 | 0.3 | X | X | Potentially Pathogenic | The guanidinium group of Arg573, located in an α-helix (res. Arg563-Glu578), forms a salt bridge with the carboxylate groups of Glu582 and/or Asp586 from a nearby α-helix (res. Glu582-Met603) in the WT simulations. Additionally, the Arg573 side chain stacks planarly with the aromatic phenol ring of Tyr665 and hydrogen bonds with the hydroxyl group of Ser668 from another α-helix (res. Ser641-Ser668). In the variant simulations, the aliphatic iso-butyl group of the Leu573 side chain fails to establish any of these interactions, which, in turn, lowers the integrity of the opposing α-helix end (res. Glu582-Met603). Overall, the residue swap has the potential to substantially affect the tertiary structure assembly during the protein folding process. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||
| c.1735C>G | R579G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R579G is reported in gnomAD (ID 6‑33440787‑C‑G) and has no ClinVar entry. Prediction tools that assess pathogenicity uniformly favor a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. No tool in the dataset reports a benign outcome; the only uncertain calls are from FoldX, AlphaMissense‑Optimized, and Foldetta. High‑accuracy assessments further support pathogenicity: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic, while AlphaMissense‑Optimized and Foldetta remain uncertain. Consequently, the collective evidence indicates that R579G is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.022872 | Uncertain | 0.877 | 0.244 | 0.000 | 6-33440787-C-G | 1 | 6.20e-7 | -14.298 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 1.43 | Ambiguous | 0.0 | 2.36 | Destabilizing | 1.90 | Ambiguous | 1.32 | Destabilizing | 0.680 | Likely Pathogenic | -5.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.40 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.3078 | 0.2554 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1736G>C | R579P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R579P is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a pathogenic effect include SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.022872 | Uncertain | 0.877 | 0.244 | 0.000 | -14.826 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.00 | Destabilizing | 0.2 | 6.36 | Destabilizing | 4.68 | Destabilizing | 0.93 | Ambiguous | 0.821 | Likely Pathogenic | -6.26 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.41 | Pathogenic | 0.01 | Affected | 0.2207 | 0.3081 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1738G>T | G580C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580C is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic outcome include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Rosetta and premPS. High‑accuracy methods all support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No tool predicts benign. **Based on the consensus of available predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status (which is currently unreported).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.025952 | Uncertain | 0.853 | 0.236 | 0.000 | -11.608 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 2.94 | Destabilizing | 0.1 | 1.18 | Ambiguous | 2.06 | Destabilizing | 0.60 | Ambiguous | 0.755 | Likely Pathogenic | -8.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.18 | Pathogenic | 0.01 | Affected | 0.1422 | 0.2146 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||
| c.1741C>T | R581W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R581W is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include only Rosetta, whereas the remaining pathogenic‑predicating tools—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—consistently classify the variant as deleterious. Uncertain or inconclusive results come from FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Pathogenic”; and Foldetta remains “Uncertain.” Overall, the preponderance of evidence points to a pathogenic impact, which contrasts with the ClinVar designation of uncertainty. 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 | Uncertain | 2 | -12.855 | Likely Pathogenic | 0.920 | Likely Pathogenic | Ambiguous | 1.32 | Ambiguous | 0.1 | -0.32 | Likely Benign | 0.50 | Ambiguous | 0.68 | Ambiguous | 0.678 | Likely Pathogenic | -6.79 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.37 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.1142 | 0.3043 | 2 | -3 | 3.6 | 30.03 | 257.8 | 36.0 | 0.1 | 0.1 | 0.1 | 0.3 | X | 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 in a slightly α-helical loop (res. Glu478-Thr488) preceding another α helix (res. Ala461-Phe476).In the variant simulations, the neutral indole ring of the Trp581 side chain cannot form any of these salt bridges. Instead, it packs hydrophobically against Met477 and Ile587 without forming any direct hydrogen bonds. The tendency of the loop (res. Asp477-Thr488) to acquire an α-helical structure seems to marginally increase, potentially due to Trp581's inability to coordinate stable hydrogen bonds with the loop residues (e.g., Glu478-Arg581 salt bridge). Additionally, the residue swap could weaken the tertiary structure assembly and negatively affect the overall protein folding process. | |||||||||||||||
| c.1747G>T | D583Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D583Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect are Foldetta and premPS, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome; FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -12.187 | Likely Pathogenic | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.75 | Ambiguous | 0.2 | -1.10 | Ambiguous | -0.18 | Likely Benign | 0.10 | Likely Benign | 0.760 | Likely Pathogenic | -8.50 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.45 | Pathogenic | 0.01 | Affected | 0.0537 | 0.3868 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1751T>A | I584N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I584N is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree that the variant is deleterious: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify it as pathogenic. No tool predicts a benign effect. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a pathogenic impact. All available predictions are concordant and supportive. Based on these computational assessments, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.059222 | Structured | 0.046673 | Uncertain | 0.846 | 0.244 | 0.000 | -13.153 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 2.70 | Destabilizing | 0.1 | 2.13 | Destabilizing | 2.42 | Destabilizing | 2.08 | Destabilizing | 0.706 | Likely Pathogenic | -6.57 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.18 | Pathogenic | 0.01 | Affected | 0.0693 | 0.0470 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.1759A>T | R587W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R587W is not reported in ClinVar and is present in gnomAD (ID 6‑33440811‑A‑T). Functional prediction tools show a split assessment: benign predictions come from FoldX, Rosetta, and Foldetta, whereas pathogenic predictions are reported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: premPS and AlphaMissense‑Optimized. High‑accuracy consensus methods further clarify the picture: the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic effect, whereas Foldetta, a protein‑folding stability predictor combining FoldX‑MD and Rosetta outputs, classifies the variant as benign. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not conflict with the ClinVar status, which currently lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.077330 | Uncertain | 0.862 | 0.216 | 0.000 | 6-33440811-A-T | 1 | 6.20e-7 | -15.383 | Likely Pathogenic | 0.879 | Likely Pathogenic | Ambiguous | -0.01 | Likely Benign | 0.1 | -0.44 | Likely Benign | -0.23 | Likely Benign | 0.76 | Ambiguous | 0.692 | Likely Pathogenic | -7.17 | Deleterious | 1.000 | Probably Damaging | 0.985 | Probably Damaging | -1.33 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1326 | 0.3992 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||
| c.1768A>C | S590R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590R is not reported in ClinVar (status: None) and has no entries in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of tools predict a pathogenic impact: SGM‑Consensus (likely pathogenic), REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are inconclusive or missing. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). 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 | 0.640 | Likely Pathogenic | -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.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.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.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.1771G>A | A591T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A591T is listed in ClinVar with an uncertain significance designation and is observed in gnomAD (variant ID 6‑33440823‑G‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from 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, reports a likely pathogenic outcome. High‑accuracy assessments further show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other folding‑stability metrics are available. Overall, the balance of evidence favors a pathogenic interpretation, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.018787 | Structured | 0.093848 | Uncertain | 0.882 | 0.185 | 0.000 | Conflicting | 3 | 6-33440823-G-A | 18 | 1.12e-5 | -9.572 | Likely Pathogenic | 0.704 | Likely Pathogenic | Likely Benign | 1.61 | Ambiguous | 0.2 | 1.00 | Ambiguous | 1.31 | Ambiguous | 1.19 | Destabilizing | 0.270 | Likely Benign | -3.40 | Deleterious | 0.955 | Possibly Damaging | 0.209 | Benign | 3.48 | Benign | 0.01 | Affected | 3.37 | 35 | 0.1225 | 0.4155 | 1 | 0 | -2.5 | 30.03 | 202.9 | -43.4 | 0.2 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | 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, the hydroxyl group of Thr591 can form hydrogen bonds with the backbone carbonyl of Ile843 in the opposing loop or the backbone carbonyl group of Arg587. These interactions could either reinforce the tertiary assembly or weaken the α helix unity. Additionally, the Thr591 side chain can hydrogen bond with the guanidinium group of the Arg587 side chain, potentially strengthening the α helix unity.Overall, the residue swap does not seem to cause any major negative effects on the protein structure. | |||||||||||||
| 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.1777C>T | L593F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L593F is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, Rosetta, and FATHMM, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions that are inconclusive—FoldX, Foldetta, premPS, and AlphaMissense‑Optimized—are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.110534 | Uncertain | 0.941 | 0.151 | 0.000 | -12.723 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 1.46 | Ambiguous | 0.4 | 0.24 | Likely Benign | 0.85 | Ambiguous | 0.62 | Ambiguous | 0.304 | Likely Benign | -3.78 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.95 | Benign | 0.01 | Affected | 0.0884 | 0.2631 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1780T>G | F594V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594V lies within the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that assess pathogenicity unanimously favor a deleterious effect: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity; only Rosetta is uncertain. No tool predicts a benign outcome. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which simply lacks an entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -12.648 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.2 | 1.90 | Ambiguous | 2.41 | Destabilizing | 1.80 | Destabilizing | 0.931 | Likely Pathogenic | -6.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.91 | Pathogenic | 0.01 | Affected | 0.1813 | 0.1575 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1781T>A | F594Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F594Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to Rosetta, which scores the substitution as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, SGM‑Consensus, and premPS all classify the variant as pathogenic. FoldX and Foldetta are uncertain, and AlphaMissense‑Optimized is also uncertain, so these results are treated as unavailable. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, while AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence indicates that F594Y 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 | 0.009187 | Structured | 0.120166 | Uncertain | 0.946 | 0.147 | 0.000 | -13.692 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.30 | Ambiguous | 0.2 | 0.41 | Likely Benign | 0.86 | Ambiguous | 1.21 | Destabilizing | 0.929 | Likely Pathogenic | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.976 | Probably Damaging | -1.98 | Pathogenic | 0.01 | Affected | 0.1264 | 0.0731 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| 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.1789T>A | F597I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -13.674 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 3.62 | Destabilizing | 0.9 | 2.15 | Destabilizing | 2.89 | Destabilizing | 1.45 | Destabilizing | 0.951 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -2.18 | Pathogenic | 0.01 | Affected | 0.2008 | 0.1815 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1789T>G | F597V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F597V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect. Benign predictions: none. Pathogenic predictions: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.142961 | Uncertain | 0.944 | 0.151 | 0.000 | -13.883 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 3.75 | Destabilizing | 0.7 | 2.02 | Destabilizing | 2.89 | Destabilizing | 1.60 | Destabilizing | 0.939 | Likely Pathogenic | -6.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -2.16 | Pathogenic | 0.01 | Affected | 0.2237 | 0.1583 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1798C>A | P600T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600T is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include Foldetta, Rosetta, and premPS. Those that predict pathogenicity are REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, while Foldetta indicates a benign effect on protein folding stability. Overall, the majority of computational evidence supports a pathogenic effect for P600T, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -11.945 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 2.61 | Destabilizing | 0.1 | -2.90 | Stabilizing | -0.15 | Likely Benign | 0.24 | Likely Benign | 0.737 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.34 | Pathogenic | 0.01 | Affected | 0.1871 | 0.4954 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.1798C>T | P600S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P600S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include Rosetta and Foldetta, whereas the majority of other in‑silico predictors (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict it to be pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as benign. No contradictory evidence exists in ClinVar. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009728 | Structured | 0.162960 | Uncertain | 0.947 | 0.147 | 0.000 | -12.002 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.54 | Destabilizing | 0.1 | -2.60 | Stabilizing | -0.03 | Likely Benign | 0.52 | Ambiguous | 0.717 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.40 | Pathogenic | 0.01 | Affected | 0.3744 | 0.4200 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||
| c.1801G>C | A601P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A601P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, while the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic. The high‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta outputs)—all report pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -14.584 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 4.90 | Destabilizing | 0.6 | 8.84 | Destabilizing | 6.87 | Destabilizing | 0.87 | Ambiguous | 0.713 | Likely Pathogenic | -4.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2176 | 0.4328 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1801G>T | A601S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools—FoldX, Rosetta, Foldetta, and premPS—return uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie and thus inconclusive. Foldetta, which integrates FoldX‑MD and Rosetta outputs, also yields an uncertain result. Overall, more tools (six) predict pathogenicity than benign (three), and no ClinVar evidence contradicts this assessment. Therefore, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | -11.248 | Likely Pathogenic | 0.136 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.21 | Ambiguous | 0.79 | Ambiguous | 0.541 | Likely Pathogenic | -2.99 | Deleterious | 0.983 | Probably Damaging | 0.993 | Probably Damaging | 2.56 | Benign | 0.01 | Affected | 0.2732 | 0.4730 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.1802C>G | A601G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A601G missense variant is listed in gnomAD (ID 6‑33440854‑C‑G) but has no ClinVar entry. Prediction tools that agree on a benign effect are FATHMM and AlphaMissense‑Optimized; those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The high‑accuracy consensus methods give a pathogenic verdict: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also pathogenic. AlphaMissense‑Default and premPS are uncertain, and no evidence is available from other folding‑stability tools. Overall, the preponderance of evidence points to a pathogenic impact for A601G, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.008895 | Structured | 0.174517 | Uncertain | 0.955 | 0.156 | 0.000 | 6-33440854-C-G | 1 | 6.19e-7 | -11.772 | Likely Pathogenic | 0.543 | Ambiguous | Likely Benign | 2.03 | Destabilizing | 0.0 | 2.31 | Destabilizing | 2.17 | Destabilizing | 0.94 | Ambiguous | 0.511 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2337 | 0.4370 | 0 | 1 | -2.2 | -14.03 | |||||||||||||||||||||||||
| c.1810T>C | S604P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also labels the variant as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence supports a pathogenic classification for S604P, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.953 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.76 | Destabilizing | 0.3 | 8.40 | Destabilizing | 6.08 | Destabilizing | 0.04 | Likely Benign | 0.512 | Likely Pathogenic | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 3.10 | Benign | 0.01 | Affected | 0.2524 | 0.4829 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1817G>T | S606I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, Rosetta, Foldetta, premPS, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic impact for S606I. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -14.552 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | -0.60 | Ambiguous | 0.1 | -0.08 | Likely Benign | -0.34 | Likely Benign | 0.41 | Likely Benign | 0.288 | Likely Benign | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.0891 | 0.4162 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.1819C>A | L607I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L607I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default, while benign calls are made by PROVEAN and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Stability predictions from FoldX, Rosetta, and premPS are inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for L607I. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -12.061 | Likely Pathogenic | 0.644 | Likely Pathogenic | Likely Benign | 0.63 | Ambiguous | 0.1 | 1.25 | Ambiguous | 0.94 | Ambiguous | 0.82 | Ambiguous | 0.727 | Likely Pathogenic | -1.99 | Neutral | 0.992 | Probably Damaging | 0.997 | Probably Damaging | -1.54 | Pathogenic | 0.01 | Affected | 0.1079 | 0.3767 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.1819C>G | L607V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L607V is listed in ClinVar with an uncertain significance (ClinVar ID 1450275.0) and is present in gnomAD (ID 6‑33440871‑C‑G). Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated algorithms—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized reports benign, whereas the SGM‑Consensus, derived from the majority of pathogenic predictions, indicates pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive and therefore not considered evidence. Overall, the preponderance of computational evidence points to a pathogenic effect for L607V, a conclusion that contrasts with the current ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | Uncertain | 2 | 6-33440871-C-G | 2 | 1.24e-6 | -11.190 | Likely Pathogenic | 0.637 | Likely Pathogenic | Likely Benign | 1.04 | Ambiguous | 0.2 | 1.36 | Ambiguous | 1.20 | Ambiguous | 0.90 | Ambiguous | 0.715 | Likely Pathogenic | -2.99 | Deleterious | 0.985 | Probably Damaging | 0.992 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1634 | 0.3577 | 2 | 1 | 0.4 | -14.03 | 216.3 | 28.1 | 0.1 | 0.0 | 0.9 | 0.2 | X | Potentially Benign | Leu607 is located in a short helical region (res. Ser606-Phe608) within an α-α loop connecting two α helices (res. Glu582-Met603 and res. Glu617-Asn635). In the WT simulations, the iso-butyl side chain of Leu607 does not interact with any other residues, but it could potentially interact directly with Ras due to its location at the GAP domain.In the variant simulations, Val607, which has similar size and physicochemical properties to leucine, does not cause any negative effects on the protein structure. However, due to its location at the GAP-Ras interface, the residue swap could affect the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | |||||||||||||
| c.1819C>T | L607F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607F is catalogued in gnomAD (6‑33440871‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all report pathogenic or likely pathogenic. Only FoldX predicts a benign outcome, while Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments show the SGM‑Consensus as likely pathogenic, AlphaMissense‑Optimized as uncertain, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for L607F, and this conclusion is not contradicted by ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | 6-33440871-C-T | 1 | 6.19e-7 | -13.654 | Likely Pathogenic | 0.948 | Likely Pathogenic | Ambiguous | 0.23 | Likely Benign | 0.1 | 1.20 | Ambiguous | 0.72 | Ambiguous | 0.61 | Ambiguous | 0.758 | Likely Pathogenic | -3.98 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.54 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0872 | 0.2816 | 0 | 2 | -1.0 | 34.02 | ||||||||||||||||||||||||
| c.1820T>A | L607H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on pathogenicity include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a benign effect. Uncertain predictions come from FoldX, Rosetta, and Foldetta. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -14.775 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.76 | Ambiguous | 0.1 | 1.88 | Ambiguous | 1.32 | Ambiguous | 1.38 | Destabilizing | 0.906 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.48 | Pathogenic | 0.01 | Affected | 0.1199 | 0.0541 | -2 | -3 | -7.0 | 23.98 | |||||||||||||||||||||||||||||
| c.1820T>G | L607R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L607R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. All other evaluated algorithms—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. Rosetta and Foldetta provide uncertain results and are therefore treated as unavailable evidence. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic,” while Foldetta remains uncertain. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.194229 | Uncertain | 0.869 | 0.250 | 0.000 | -14.234 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | -0.15 | Likely Benign | 0.1 | 1.48 | Ambiguous | 0.67 | Ambiguous | 1.24 | Destabilizing | 0.920 | Likely Pathogenic | -5.98 | Deleterious | 0.998 | Probably Damaging | 0.998 | Probably Damaging | -1.51 | Pathogenic | 0.01 | Affected | 0.1490 | 0.0615 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||
| c.1822T>C | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. FoldX and Foldetta report uncertain stability changes, but these are not considered evidence against pathogenicity. When predictions are grouped, no tool predicts a benign outcome; all available evidence supports a harmful effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from the majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.883 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1822T>G | F608V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a pathogenic effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; all of these return a pathogenic or likely pathogenic label. No tool in the dataset predicts a benign outcome. Uncertain results are reported only for Rosetta and Foldetta, which are treated as unavailable evidence. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Taken together, the overwhelming majority of predictions indicate that F608V is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -16.084 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 2.21 | Destabilizing | 0.1 | 1.39 | Ambiguous | 1.80 | Ambiguous | 1.47 | Destabilizing | 0.917 | Likely Pathogenic | -6.97 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | -1.59 | Pathogenic | 0.01 | Affected | 0.2193 | 0.2199 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.1824T>A | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. FoldX and Foldetta report uncertain stability changes, but these are not considered evidence against pathogenicity. When predictions are grouped, no tool predicts a benign outcome; all available evidence supports a harmful effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (derived from the majority of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic, and Foldetta remains inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.747 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1824T>G | F608L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F608L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a deleterious effect: SGM‑Consensus, REVEL, FoldX‑MD (uncertain), Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while only FoldX and Foldetta are inconclusive. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labels it likely pathogenic, and Foldetta reports an uncertain stability change. No tool predicts a benign outcome. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.106997 | Structured | 0.197190 | Uncertain | 0.891 | 0.247 | 0.000 | -12.274 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.86 | Ambiguous | 0.2 | 2.59 | Destabilizing | 1.73 | Ambiguous | 1.24 | Destabilizing | 0.747 | Likely Pathogenic | -5.97 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | -1.50 | Pathogenic | 0.01 | Affected | 0.2231 | 0.2874 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.1825G>T | G609W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609W (ClinVar ID 4327030) is not found in gnomAD. Prediction tools that classify the variant as benign include premPS and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM) predict it to be pathogenic; Rosetta, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence from pathogenic‑oriented tools and the SGM Consensus supports a pathogenic effect, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | 1 | -13.074 | Likely Pathogenic | 0.525 | Ambiguous | Likely Benign | 3.14 | Destabilizing | 0.7 | -0.87 | Ambiguous | 1.14 | Ambiguous | 0.28 | Likely Benign | 0.566 | Likely Pathogenic | -4.70 | Deleterious | 0.999 | Probably Damaging | 0.976 | Probably Damaging | -1.47 | Pathogenic | 0.01 | Affected | 0.0935 | 0.3181 | -7 | -2 | -0.5 | 129.16 | ||||||||||||||||||||||||||||
| c.1828C>G | L610V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L610V is reported in gnomAD (ID 6‑33440880‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic calls are made by REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM, while only AlphaMissense‑Optimized predicts a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support this view: AlphaMissense‑Optimized indicates benign, whereas the SGM Consensus remains pathogenic and Foldetta (combining FoldX‑MD and Rosetta) is inconclusive. With the overwhelming majority of tools predicting pathogenicity and no ClinVar evidence to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | 6-33440880-C-G | 3 | 1.86e-6 | -11.304 | Likely Pathogenic | 0.474 | Ambiguous | Likely Benign | 2.24 | Destabilizing | 0.3 | 0.76 | Ambiguous | 1.50 | Ambiguous | 1.21 | Destabilizing | 0.740 | Likely Pathogenic | -2.86 | Deleterious | 0.985 | Probably Damaging | 0.992 | Probably Damaging | -1.46 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.1515 | 0.3039 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.1828C>T | L610F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L610F is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—all of which classify the variant as pathogenic. No tools predict a benign outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Based on the consensus of these predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.271506 | Structured | 0.209504 | Uncertain | 0.888 | 0.253 | 0.000 | -13.244 | Likely Pathogenic | 0.808 | Likely Pathogenic | Ambiguous | 6.24 | Destabilizing | 1.1 | 3.40 | Destabilizing | 4.82 | Destabilizing | 0.68 | Ambiguous | 0.782 | Likely Pathogenic | -3.92 | Deleterious | 0.998 | Probably Damaging | 0.997 | Probably Damaging | -1.52 | Pathogenic | 0.01 | Affected | 0.0834 | 0.2816 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.1838A>G | E613G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E613G is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include only premPS, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) uniformly predict a pathogenic impact. The high‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain. No prediction or stability assessment is missing or inconclusive beyond the uncertain labels. Overall, the preponderance of evidence points to a pathogenic effect for E613G, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.193489 | Uncertain | 0.816 | 0.254 | 0.000 | -12.417 | Likely Pathogenic | 0.911 | Likely Pathogenic | Ambiguous | 1.49 | Ambiguous | 0.3 | 1.34 | Ambiguous | 1.42 | Ambiguous | 0.08 | Likely Benign | 0.641 | Likely Pathogenic | -6.56 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.26 | Pathogenic | 0.01 | Affected | 0.3422 | 0.5266 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1844C>A | P615Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change P615Q is not listed in ClinVar and has no allele record in gnomAD. Functional prediction tools that assess sequence conservation and structural impact uniformly classify the variant as pathogenic: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only Rosetta and the combined Foldetta stability assessment are inconclusive. Grouping the predictions, the benign category contains no tools, while the pathogenic category includes all the above. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports Likely Pathogenic, and Foldetta remains uncertain. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -13.247 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.16 | Destabilizing | 0.3 | 1.28 | Ambiguous | 1.72 | Ambiguous | 1.33 | Destabilizing | 0.742 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -1.28 | Pathogenic | 0.01 | Affected | 0.1395 | 0.3445 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||
| c.1844C>G | P615R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P615R is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. No predictions or stability results are missing or inconclusive. Based on the unanimous pathogenic predictions and the absence of any ClinVar or gnomAD evidence to the contrary, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.236433 | Structured | 0.179032 | Uncertain | 0.879 | 0.255 | 0.000 | -15.628 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.62 | Destabilizing | 0.5 | 2.69 | Destabilizing | 2.66 | Destabilizing | 1.14 | Destabilizing | 0.871 | Likely Pathogenic | -8.96 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.29 | Pathogenic | 0.01 | Affected | 0.1463 | 0.2603 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.1846G>T | D616Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D616Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas a majority of tools predict a pathogenic outcome: SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | -12.638 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 1.70 | Ambiguous | 0.3 | 1.32 | Ambiguous | 1.51 | Ambiguous | 0.35 | Likely Benign | 0.374 | Likely Benign | -7.43 | Deleterious | 0.999 | Probably Damaging | 0.970 | Probably Damaging | 3.28 | Benign | 0.01 | Affected | 0.0465 | 0.4069 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||
| c.1861C>G | R621G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621G is reported in gnomAD (ID 6‑33440913‑C‑G) but has no ClinVar entry. In silico predictors largely agree on a deleterious effect: pathogenic calls come from REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only benign prediction is from FATHMM; FoldX and Foldetta give uncertain results. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | 6-33440913-C-G | 1 | 6.20e-7 | -16.611 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.18 | Ambiguous | 0.3 | 2.07 | Destabilizing | 1.63 | Ambiguous | 1.17 | Destabilizing | 0.558 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.84 | Benign | 0.01 | Affected | 3.37 | 35 | 0.3109 | 0.2651 | -2 | -3 | 4.1 | -99.14 | ||||||||||||||||||||||||
| c.1862G>A | R621Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R621Q is listed in ClinVar (ID 578137.0) as benign and is present in gnomAD (variant ID 6‑33440914‑G‑A). Functional prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—REVEL, 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, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX, Rosetta, or Foldetta supports a benign outcome. Overall, the preponderance of predictions indicates a likely pathogenic effect, which contradicts the benign classification reported in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | Likely Benign | 1 | 6-33440914-G-A | 19 | 1.18e-5 | -14.682 | Likely Pathogenic | 0.910 | Likely Pathogenic | Ambiguous | 0.81 | Ambiguous | 0.1 | 1.13 | Ambiguous | 0.97 | Ambiguous | 1.35 | Destabilizing | 0.621 | Likely Pathogenic | -3.98 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.82 | Benign | 0.01 | Affected | 3.37 | 35 | 0.2590 | 0.1963 | 1 | 1 | 1.0 | -28.06 | 243.7 | 54.3 | 0.0 | 0.0 | -0.4 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg621, located in an α helix (res. Glu617-Asn635), forms a salt bridge with Glu525 in a nearby loop and stacks with Leu635. In the variant simulations, the carboxamide side chain of Gln621, which can act as both a hydrogen bond acceptor and donor, also stacks with Leu635 but can only sporadically hydrogen bond with Glu525.Accordingly, the residue swap could affect the tertiary structure integrity by disrupting the salt bridge formation. Additionally, due to its location at the GAP-Ras interface, the residue swap could impact the complex formation with the GTPase, but this cannot be investigated using solvent-only simulations. | ||||||||||||
| c.1862G>C | R621P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R621P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining eleven tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. The high‑accuracy subset further supports this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenic. No prediction is inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently contains no entry for R621P. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.084420 | Uncertain | 0.945 | 0.216 | 0.000 | -17.022 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.94 | Destabilizing | 0.4 | 9.39 | Destabilizing | 7.17 | Destabilizing | 0.96 | Ambiguous | 0.745 | Likely Pathogenic | -6.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.81 | Benign | 0.01 | Affected | 0.2143 | 0.3692 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.1864A>C | T622P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T622P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as pathogenic. No tool predicts a benign outcome; the only inconclusive result is premPS, which is listed as uncertain. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also indicates pathogenic. Consequently, the variant is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -16.410 | Likely Pathogenic | 0.964 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.4 | 8.90 | Destabilizing | 5.86 | Destabilizing | 0.78 | Ambiguous | 0.924 | Likely Pathogenic | -5.57 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.57 | Pathogenic | 0.01 | Affected | 0.1700 | 0.3876 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1864A>G | T622A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T622A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only FoldX, which scores the variant as benign. In contrast, the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools with uncertain or inconclusive results—AlphaMissense‑Optimized, Rosetta, Foldetta, and premPS—are treated as unavailable for pathogenicity assessment. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for T622A, 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 | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -10.953 | Likely Pathogenic | 0.827 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | 1.04 | Ambiguous | 0.54 | Ambiguous | 0.75 | Ambiguous | 0.893 | Likely Pathogenic | -4.58 | Deleterious | 0.998 | Probably Damaging | 0.989 | Probably Damaging | -1.52 | Pathogenic | 0.01 | Affected | 0.3191 | 0.3091 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||
| 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.1870A>C | T624P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T624P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -15.681 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 3.64 | Destabilizing | 0.2 | 9.04 | Destabilizing | 6.34 | Destabilizing | 0.83 | Ambiguous | 0.914 | Likely Pathogenic | -5.94 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -1.55 | Pathogenic | 0.01 | Affected | 0.1500 | 0.3569 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.1870A>T | T624S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T624S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -13.314 | Likely Pathogenic | 0.766 | Likely Pathogenic | Likely Benign | -0.10 | Likely Benign | 0.1 | 0.95 | Ambiguous | 0.43 | Likely Benign | 0.69 | Ambiguous | 0.761 | Likely Pathogenic | -3.93 | Deleterious | 0.826 | Possibly Damaging | 0.789 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 0.2326 | 0.2813 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.1871C>G | T624S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T624S missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Rosetta and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none is present). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -13.314 | Likely Pathogenic | 0.766 | Likely Pathogenic | Likely Benign | -0.10 | Likely Benign | 0.1 | 0.95 | Ambiguous | 0.43 | Likely Benign | 0.69 | Ambiguous | 0.734 | Likely Pathogenic | -3.93 | Deleterious | 0.826 | Possibly Damaging | 0.789 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 0.2326 | 0.2813 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| 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.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.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.1879G>A | A627T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A627T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—consistently predict a pathogenic impact. Two tools, premPS and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict, and Foldetta also predicts a destabilizing, pathogenic effect. AlphaMissense‑Optimized remains uncertain. Overall, the preponderance of evidence indicates that A627T is most likely pathogenic, 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 | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -8.613 | Likely Pathogenic | 0.937 | Likely Pathogenic | Ambiguous | 2.27 | Destabilizing | 0.3 | 2.33 | Destabilizing | 2.30 | Destabilizing | 0.80 | Ambiguous | 0.505 | Likely Pathogenic | -3.95 | Deleterious | 0.994 | Probably Damaging | 0.807 | Possibly Damaging | 2.56 | Benign | 0.01 | Affected | 0.1069 | 0.5403 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1879G>C | A627P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A627P is not reported in ClinVar and is absent from gnomAD. Prediction tools were grouped by consensus: Benign – none; Pathogenic – SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized. High‑accuracy methods specifically: AlphaMissense‑Optimized predicts pathogenicity; SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic; Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a deleterious 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 | GAP | 0.100716 | Structured | 0.037862 | Uncertain | 0.970 | 0.210 | 0.000 | -15.404 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 5.78 | Destabilizing | 0.3 | 7.84 | Destabilizing | 6.81 | Destabilizing | 1.13 | Destabilizing | 0.740 | Likely Pathogenic | -4.96 | Deleterious | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.43 | Pathogenic | 0.01 | Affected | 0.1752 | 0.3422 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| 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.1888A>T | I630F 2D 3DClick to see structure in 3D Viewer AISynGAP1 I630F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. Those that agree on a pathogenic effect comprise SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, Foldetta, and premPS and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicting likely pathogenic, and Foldetta yielding an uncertain stability change. Overall, the preponderance of evidence points to a pathogenic impact for I630F. This conclusion is not contradicted by ClinVar, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.036106 | Uncertain | 0.966 | 0.236 | 0.000 | -13.669 | Likely Pathogenic | 0.705 | Likely Pathogenic | Likely Benign | 2.52 | Destabilizing | 0.3 | 0.76 | Ambiguous | 1.64 | Ambiguous | 0.75 | Ambiguous | 0.782 | Likely Pathogenic | -3.12 | Deleterious | 0.935 | Possibly Damaging | 0.473 | Possibly Damaging | -1.46 | Pathogenic | 0.01 | Affected | 0.0443 | 0.1964 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.1891C>A | Q631K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q631K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Foldetta, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score. Uncertain or inconclusive results are reported by Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy methods give a mixed picture: Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect; the SGM‑Consensus, a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely pathogenic outcome; AlphaMissense‑Optimized remains uncertain. Overall, the majority of evidence points toward a pathogenic impact, 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 | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -15.194 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | -0.37 | Likely Benign | 0.1 | 1.13 | Ambiguous | 0.38 | Likely Benign | 0.88 | Ambiguous | 0.596 | Likely Pathogenic | -3.98 | Deleterious | 0.958 | Probably Damaging | 0.931 | Probably Damaging | 2.79 | Benign | 0.01 | Affected | 0.1288 | 0.2157 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.1891C>G | Q631E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying it as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) yielding an uncertain result. Overall, the majority of evidence (eight pathogenic predictions versus three benign) points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which is currently unavailable. 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 | -15.628 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 1.55 | Ambiguous | 0.80 | Ambiguous | 0.95 | Ambiguous | 0.532 | Likely Pathogenic | -2.99 | Deleterious | 0.997 | Probably Damaging | 0.981 | Probably Damaging | 2.78 | Benign | 0.01 | Affected | 0.1068 | 0.1264 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1892A>G | Q631R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q631R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: benign predictions come from FoldX, Foldetta, and FATHMM, while pathogenic predictions are made by SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact for Q631R, and this conclusion is not contradicted by any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.038963 | Uncertain | 0.948 | 0.230 | 0.000 | -14.881 | Likely Pathogenic | 0.958 | Likely Pathogenic | Likely Pathogenic | -0.34 | Likely Benign | 0.1 | 0.83 | Ambiguous | 0.25 | Likely Benign | 0.77 | Ambiguous | 0.627 | Likely Pathogenic | -3.98 | Deleterious | 0.973 | Probably Damaging | 0.969 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.1193 | 0.0653 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.1894A>G | N632D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N632D is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic effect, while SGM‑Consensus also indicates a likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, SGM‑Consensus remains likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Because the majority of evidence points to deleterious impact and there is no ClinVar annotation to contradict this, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | -14.117 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | 1.84 | Ambiguous | 0.4 | 1.50 | Ambiguous | 1.67 | Ambiguous | 1.09 | Destabilizing | 0.827 | Likely Pathogenic | -4.31 | Deleterious | 0.985 | Probably Damaging | 0.776 | Possibly Damaging | -1.53 | Pathogenic | 0.01 | Affected | 0.1791 | 0.3854 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.1896C>A | N632K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632K is not reported in ClinVar and is present in gnomAD. Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify it as pathogenic; premPS is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the preponderance of evidence points to a pathogenic effect for N632K, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | 6-33440948-C-A | -13.266 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.12 | Likely Benign | 0.03 | Likely Benign | 0.95 | Ambiguous | 0.766 | Likely Pathogenic | -5.14 | Deleterious | 0.983 | Probably Damaging | 0.714 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.2375 | 0.4897 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1896C>G | N632K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the majority of 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 | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | -13.266 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.12 | Likely Benign | 0.03 | Likely Benign | 0.95 | Ambiguous | 0.766 | Likely Pathogenic | -5.14 | Deleterious | 0.983 | Probably Damaging | 0.714 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.2375 | 0.4897 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||
| c.1897C>A | L633M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633M has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, premPS) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta is also inconclusive. Overall, the majority of definitive predictions (5 pathogenic vs. 4 benign) lean toward 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. | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | -10.300 | Likely Pathogenic | 0.718 | Likely Pathogenic | Likely Benign | 0.61 | Ambiguous | 0.1 | 1.47 | Ambiguous | 1.04 | Ambiguous | 0.90 | Ambiguous | 0.355 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.0984 | 0.2683 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1900G>A | A634T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634T is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a pathogenic effect: SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, while only FATHMM predicts benign. Two tools give uncertain results: AlphaMissense‑Optimized and Foldetta. High‑accuracy assessment shows that the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic classification, whereas AlphaMissense‑Optimized and Foldetta remain inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for A634T, 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 | 0.085092 | Structured | 0.052058 | Uncertain | 0.932 | 0.242 | 0.000 | -12.451 | Likely Pathogenic | 0.946 | Likely Pathogenic | Ambiguous | 2.56 | Destabilizing | 0.1 | 1.11 | Ambiguous | 1.84 | Ambiguous | 1.34 | Destabilizing | 0.603 | Likely Pathogenic | -3.98 | Deleterious | 0.994 | Probably Damaging | 0.986 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.1397 | 0.5240 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.1900G>C | A634P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a deleterious effect: benign predictions are limited to FATHMM, 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 reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as none is available. 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 | -15.372 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.17 | Destabilizing | 0.2 | 7.72 | Destabilizing | 5.95 | Destabilizing | 1.39 | Destabilizing | 0.745 | Likely Pathogenic | -4.98 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.50 | Benign | 0.01 | Affected | 0.2090 | 0.3429 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.1901C>T | A634V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A634V is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score, while only FATHMM predicts a benign outcome; Rosetta remains inconclusive. High‑accuracy assessments reinforce the pathogenic trend: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Taken together, the overwhelming majority of evidence supports a pathogenic effect for A634V, which is in contrast to its current ClinVar classification of uncertain significance. Therefore, the variant is most likely pathogenic, contradicting its ClinVar uncertain status. 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 | Uncertain | 1 | -12.612 | Likely Pathogenic | 0.971 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.2 | 1.44 | Ambiguous | 2.06 | Destabilizing | 1.14 | Destabilizing | 0.631 | Likely Pathogenic | -3.98 | Deleterious | 0.997 | Probably Damaging | 0.976 | Probably Damaging | 2.55 | Benign | 0.01 | Affected | 0.1215 | 0.4371 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||
| 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.1910C>G | S637C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637C 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, Foldetta, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; Foldetta predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign impact, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -10.040 | Likely Pathogenic | 0.138 | Likely Benign | Likely Benign | 0.25 | Likely Benign | 0.0 | 0.54 | Ambiguous | 0.40 | Likely Benign | 0.22 | Likely Benign | 0.169 | Likely Benign | -2.83 | Deleterious | 0.985 | Probably Damaging | 0.533 | Possibly Damaging | 3.34 | Benign | 0.01 | Affected | 0.1327 | 0.4439 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.1910C>T | S637F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S637F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, FoldX, Foldetta, premPS, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by Rosetta and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a pathogenic verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. AlphaMissense‑Optimized remains inconclusive. Overall, the majority of evidence points toward a pathogenic impact, 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 | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -13.266 | Likely Pathogenic | 0.831 | Likely Pathogenic | Ambiguous | 0.01 | Likely Benign | 0.1 | 0.96 | Ambiguous | 0.49 | Likely Benign | 0.49 | Likely Benign | 0.222 | Likely Benign | -3.92 | Deleterious | 0.985 | Probably Damaging | 0.681 | Possibly Damaging | 3.35 | Benign | 0.01 | Affected | 0.0780 | 0.4126 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||
| c.1913A>T | K638M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K638M missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, FATHMM, premPS, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized and Rosetta give uncertain results, which are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.098064 | Uncertain | 0.937 | 0.260 | 0.000 | -9.702 | Likely Pathogenic | 0.882 | Likely Pathogenic | Ambiguous | -0.21 | Likely Benign | 0.0 | 0.61 | Ambiguous | 0.20 | Likely Benign | 0.09 | Likely Benign | 0.526 | Likely Pathogenic | -5.19 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.41 | Benign | 0.01 | Affected | 0.0929 | 0.2896 | 0 | -1 | 5.8 | 3.02 | |||||||||||||||||||||||||||||
| c.1915T>A | F639I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FATHMM and Rosetta, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none reported). 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 | -12.548 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 4.32 | Destabilizing | 0.3 | 0.47 | Likely Benign | 2.40 | Destabilizing | 1.44 | Destabilizing | 0.545 | Likely Pathogenic | -5.98 | Deleterious | 0.994 | Probably Damaging | 0.659 | Possibly Damaging | 3.08 | Benign | 0.01 | Affected | 0.2070 | 0.1755 | 1 | 0 | 1.7 | -34.02 | |||||||||||||||||||||||||||||
| c.1916T>G | F639C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F639C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, and ESM1b all indicate pathogenicity, while only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change 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 calculations, also predicts a pathogenic effect. No predictions are missing or inconclusive. 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 | 0.038042 | Structured | 0.117665 | Uncertain | 0.942 | 0.284 | 0.000 | -12.532 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 4.02 | Destabilizing | 0.2 | 2.80 | Destabilizing | 3.41 | Destabilizing | 1.38 | Destabilizing | 0.615 | Likely Pathogenic | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.935 | Probably Damaging | 3.05 | Benign | 0.01 | Affected | 0.2451 | 0.0783 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1927G>C | E643Q 2D AIThe SynGAP1 missense variant E643Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized predicts a benign outcome, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of predictions (8 benign vs. 5 pathogenic) and the two of three high‑accuracy tools favor a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.404 | Likely Pathogenic | 0.688 | Likely Pathogenic | Likely Benign | 0.49 | Likely Benign | 0.6 | 0.15 | Likely Benign | 0.32 | Likely Benign | 0.83 | Ambiguous | 0.341 | Likely Benign | -2.86 | Deleterious | 0.446 | Benign | 0.038 | Benign | 2.94 | Benign | 0.01 | Affected | 0.1603 | 0.6308 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.1928A>C | E643A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643A is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. FoldX and Foldetta give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of tools lean toward a benign interpretation, and this assessment does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -12.562 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 0.80 | Ambiguous | 0.2 | 0.39 | Likely Benign | 0.60 | Ambiguous | 0.21 | Likely Benign | 0.469 | Likely Benign | -5.81 | Deleterious | 0.771 | Possibly Damaging | 0.233 | Benign | 2.92 | Benign | 0.01 | Affected | 0.4074 | 0.6096 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||
| c.1929G>C | E643D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen2_HumVar. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen2_HumDiv, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of predictions (8 benign vs. 5 pathogenic) support a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -8.083 | Likely Pathogenic | 0.223 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.2 | -0.34 | Likely Benign | 0.06 | Likely Benign | 1.09 | Destabilizing | 0.292 | Likely Benign | -2.96 | Deleterious | 0.694 | Possibly Damaging | 0.064 | Benign | 2.98 | Benign | 0.01 | Affected | 0.2040 | 0.4276 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1929G>T | E643D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E643D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen2_HumVar. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen2_HumDiv, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of predictions (8 benign vs. 5 pathogenic) support a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.033407 | Structured | 0.215915 | Uncertain | 0.871 | 0.315 | 0.000 | -8.083 | Likely Pathogenic | 0.223 | Likely Benign | Likely Benign | 0.46 | Likely Benign | 0.2 | -0.34 | Likely Benign | 0.06 | Likely Benign | 1.09 | Destabilizing | 0.292 | Likely Benign | -2.96 | Deleterious | 0.694 | Possibly Damaging | 0.064 | Benign | 2.98 | Benign | 0.01 | Affected | 0.2040 | 0.4276 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||
| c.1934T>G | F645C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F645C is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of tools predict a pathogenic outcome: FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is inconclusive. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also pathogenic. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.046336 | Structured | 0.276445 | Uncertain | 0.921 | 0.325 | 0.000 | -9.182 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 2.25 | Destabilizing | 0.1 | 2.44 | Destabilizing | 2.35 | Destabilizing | 1.38 | Destabilizing | 0.286 | Likely Benign | -5.41 | Deleterious | 0.967 | Probably Damaging | 0.389 | Benign | 3.35 | Benign | 0.01 | Affected | 0.2421 | 0.1372 | -4 | -2 | -0.3 | -44.04 | |||||||||||||||||||||||||||||
| c.1946T>A | M649K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M649K is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Benign calls are limited to polyPhen‑2 (HumVar) and FATHMM. High‑accuracy methods reinforce the pathogenic consensus: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among these tools, 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 | 0.051831 | Structured | 0.360413 | Uncertain | 0.962 | 0.345 | 0.000 | -14.533 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.0 | 6.19 | Destabilizing | 4.81 | Destabilizing | 1.79 | Destabilizing | 0.614 | Likely Pathogenic | -5.98 | Deleterious | 0.968 | Probably Damaging | 0.382 | Benign | 3.34 | Benign | 0.01 | Affected | 0.1438 | 0.1079 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| 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.1957C>A | L653M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L653M has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Tools with uncertain or missing results (FoldX, Rosetta, Foldetta, premPS) are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs. two benign votes), and Foldetta is also inconclusive. Overall, the majority of standard predictors lean toward pathogenicity, but the most reliable high‑accuracy tool indicates a benign effect, leaving the variant’s impact uncertain. No ClinVar entry exists, so there is no contradiction with clinical annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -8.838 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.99 | Ambiguous | 0.2 | 1.70 | Ambiguous | 1.35 | Ambiguous | 0.94 | Ambiguous | 0.259 | Likely Benign | -1.76 | Neutral | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.13 | Benign | 0.01 | Affected | 0.0935 | 0.3227 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.1958T>A | L653Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L653Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -14.347 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.71 | Destabilizing | 0.1 | 3.26 | Destabilizing | 2.99 | Destabilizing | 1.98 | Destabilizing | 0.614 | Likely Pathogenic | -5.65 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.1195 | 0.1363 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1961A>G | E654G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign impact are premPS and FATHMM, while the majority (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for E654G. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -12.487 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 1.29 | Ambiguous | 0.2 | 1.62 | Ambiguous | 1.46 | Ambiguous | 0.34 | Likely Benign | 0.547 | Likely Pathogenic | -6.73 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.2818 | 0.3109 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.1961A>T | E654V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E654V missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include Rosetta, Foldetta, premPS, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and AlphaMissense‑Optimized are inconclusive. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta predicts benign. Overall, the majority of tools (8 pathogenic vs. 4 benign) and the SGM‑Consensus result support a pathogenic classification. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.026892 | Structured | 0.303029 | Uncertain | 0.957 | 0.311 | 0.000 | -12.306 | Likely Pathogenic | 0.950 | Likely Pathogenic | Ambiguous | 0.55 | Ambiguous | 0.0 | -0.33 | Likely Benign | 0.11 | Likely Benign | 0.21 | Likely Benign | 0.540 | Likely Pathogenic | -6.66 | Deleterious | 0.988 | Probably Damaging | 0.734 | Possibly Damaging | 3.31 | Benign | 0.01 | Affected | 0.0686 | 0.4757 | -2 | -2 | 7.7 | -29.98 | |||||||||||||||||||||||||||||
| c.1982A>C | Q661P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q661P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from premPS and FATHMM, whereas the remaining 12 tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score) all classify the change as pathogenic or likely pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a pathogenic effect. No prediction is inconclusive. 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 | 0.048328 | Structured | 0.117089 | Uncertain | 0.924 | 0.309 | 0.000 | -17.549 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 4.11 | Destabilizing | 0.1 | 5.97 | Destabilizing | 5.04 | Destabilizing | 0.45 | Likely Benign | 0.531 | Likely Pathogenic | -4.58 | Deleterious | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 3.41 | Benign | 0.01 | Affected | 0.1811 | 0.3850 | 0 | -1 | 1.9 | -31.01 | |||||||||||||||||||||||||||||
| c.1987T>C | F663L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F663L is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, which scores the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, Rosetta, 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 (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity, while Foldetta’s stability analysis is inconclusive and therefore unavailable. FoldX and Foldetta are treated as unavailable due to uncertain outputs. Based on the overwhelming agreement among pathogenic predictors and the lack of benign evidence, 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 | 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 | 0.540 | Likely Pathogenic | -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>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.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.1990T>G | L664V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L664V is not 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, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Rosetta and Foldetta are uncertain, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic (3 pathogenic vs 1 benign). Foldetta’s stability prediction is uncertain. Overall, the majority of reliable tools predict a pathogenic impact. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.100716 | Structured | 0.089318 | Uncertain | 0.937 | 0.339 | 0.000 | -11.515 | Likely Pathogenic | 0.755 | Likely Pathogenic | Likely Benign | 2.01 | Destabilizing | 0.1 | 1.13 | Ambiguous | 1.57 | Ambiguous | 1.37 | Destabilizing | 0.378 | Likely Benign | -2.99 | Deleterious | 0.993 | Probably Damaging | 0.776 | Possibly Damaging | 2.91 | Benign | 0.01 | Affected | 0.0984 | 0.2628 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| 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.2011G>C | D671H 2D 3DClick to see structure in 3D Viewer AISynGAP1 D671H is not reported in ClinVar and is absent from gnomAD. Benign predictions are provided by REVEL, FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy tools give mixed results: AlphaMissense‑Optimized is uncertain, SGM Consensus predicts pathogenic, and Foldetta predicts benign. Overall, the balance of evidence leans toward pathogenicity, 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 | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -11.501 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.0 | 0.29 | Likely Benign | 0.39 | Likely Benign | 0.09 | Likely Benign | 0.300 | Likely Benign | -4.35 | Deleterious | 0.999 | Probably Damaging | 0.939 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.1627 | 0.6509 | 1 | -1 | 0.3 | 22.05 | |||||||||||||||||||||||||||||
| c.2012A>G | D671G 2D AIThe SynGAP1 D671G 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, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. 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. No evidence from these tools contradicts the pathogenic prediction. Overall, the balance of evidence favors a pathogenic classification for D671G, and this conclusion is consistent with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -10.346 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.50 | Ambiguous | 0.5 | 1.53 | Ambiguous | 1.02 | Ambiguous | 0.00 | Likely Benign | 0.279 | Likely Benign | -4.78 | Deleterious | 0.995 | Probably Damaging | 0.946 | Probably Damaging | 3.45 | Benign | 0.01 | Affected | 0.4032 | 0.5823 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.2012A>T | D671V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D671V missense variant 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, premPS, and FATHMM. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus methods give a pathogenic signal: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the majority of predictions (seven pathogenic vs. three benign) support a pathogenic classification. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -12.376 | Likely Pathogenic | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.1 | 0.51 | Ambiguous | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.379 | Likely Benign | -6.08 | Deleterious | 0.975 | Probably Damaging | 0.885 | Possibly Damaging | 3.31 | Benign | 0.01 | Affected | 0.0820 | 0.6651 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.2014A>C | T672P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T672P 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results come from 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 pathogenic. No predictions are missing or inconclusive. Overall, the majority of evidence points to a pathogenic impact for T672P. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.116183 | Structured | 0.102069 | Uncertain | 0.586 | 0.362 | 0.000 | -11.022 | Likely Pathogenic | 0.346 | Ambiguous | Likely Benign | 2.22 | Destabilizing | 0.2 | 5.54 | Destabilizing | 3.88 | Destabilizing | 0.55 | Ambiguous | 0.087 | Likely Benign | -4.20 | Deleterious | 0.968 | Probably Damaging | 0.824 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.1988 | 0.5532 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| 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.2026A>T | S676C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676C 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, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen2_HumVar, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen2_HumDiv, SIFT, and ESM1b. Rosetta and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. 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 available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -9.230 | Likely Pathogenic | 0.132 | Likely Benign | Likely Benign | 0.47 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.62 | Ambiguous | 0.15 | Likely Benign | 0.164 | Likely Benign | -2.45 | Neutral | 0.959 | Probably Damaging | 0.431 | Benign | 3.35 | Benign | 0.01 | Affected | 0.1113 | 0.6352 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.2032A>T | S678C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678C 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, Foldetta, premPS, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Tools with uncertain results are Rosetta and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign (2 benign vs. 1 pathogenic, 1 uncertain), and Foldetta also predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the preponderance of evidence indicates the variant is most likely benign, 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. | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -7.879 | In-Between | 0.095 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.2 | 0.55 | Ambiguous | 0.38 | Likely Benign | 0.35 | Likely Benign | 0.094 | Likely Benign | -3.31 | Deleterious | 0.947 | Possibly Damaging | 0.527 | Possibly Damaging | 3.37 | Benign | 0.01 | Affected | 0.1080 | 0.5875 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.2033G>T | S678I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678I is not 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, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence (10 benign vs. 3 pathogenic) supports a benign classification. This consensus 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 | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -9.735 | Likely Pathogenic | 0.253 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.3 | -0.01 | Likely Benign | 0.18 | Likely Benign | -0.11 | Likely Benign | 0.119 | Likely Benign | -3.99 | Deleterious | 0.294 | Benign | 0.057 | Benign | 3.45 | Benign | 0.01 | Affected | 0.0941 | 0.5954 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||
| 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.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.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.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.2042G>T | G681V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G681V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the majority of algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—classify the change as pathogenic. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; SGM‑Consensus predicts a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a pathogenic outcome. No other high‑confidence predictions are available. Taken together, the consensus of pathogenic predictions outweighs the single benign call, indicating that G681V is most likely pathogenic. This assessment is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -14.043 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 3.21 | Destabilizing | 2.0 | 6.12 | Destabilizing | 4.67 | Destabilizing | 0.64 | Ambiguous | 0.572 | Likely Pathogenic | -8.98 | Deleterious | 0.999 | Probably Damaging | 0.928 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0.1350 | 0.3840 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.2044T>G | Y682D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic. The high‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a pathogenic effect. With no ClinVar assertion to oppose these findings, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -15.094 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 2.81 | Destabilizing | 0.4 | 3.06 | Destabilizing | 2.94 | Destabilizing | 0.96 | Ambiguous | 0.639 | Likely Pathogenic | -9.60 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.32 | Benign | 0.01 | Affected | 0.4191 | 0.0760 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.2045A>G | Y682C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y682C is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, while only FATHMM predicts a benign outcome. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) are uncertain. High‑accuracy assessments reinforce this trend: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; AlphaMissense‑Optimized is uncertain; and Foldetta is uncertain. Overall, the preponderance of evidence points to a pathogenic impact for Y682C. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.206376 | Structured | 0.141467 | Uncertain | 0.758 | 0.328 | 0.000 | -10.023 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 1.79 | Ambiguous | 0.1 | 1.51 | Ambiguous | 1.65 | Ambiguous | 1.11 | Destabilizing | 0.559 | Likely Pathogenic | -8.71 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0.2949 | 0.2399 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||
| c.2047A>T | I683F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, while AlphaMissense‑Optimized and Foldetta are inconclusive and thus treated as unavailable evidence. Overall, the balance of evidence favors a pathogenic classification for I683F, and this assessment does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.781 | Likely Pathogenic | 0.828 | Likely Pathogenic | Ambiguous | 1.38 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.58 | Ambiguous | 0.59 | Ambiguous | 0.481 | Likely Benign | -3.99 | Deleterious | 0.971 | Probably Damaging | 0.499 | Possibly Damaging | 3.27 | Benign | 0.01 | Affected | 0.0770 | 0.2307 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.2048T>A | I683N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I683N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict pathogenicity, whereas only FATHMM predicts a benign outcome. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized returns a pathogenic score, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is labeled Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) also indicates pathogenicity. No predictions are missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -12.120 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 2.18 | Destabilizing | 0.1 | 2.08 | Destabilizing | 2.13 | Destabilizing | 1.46 | Destabilizing | 0.546 | Likely Pathogenic | -6.87 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 3.26 | Benign | 0.01 | Affected | 0.0978 | 0.1133 | -2 | -3 | -8.0 | 0.94 | |||||||||||||||||||||||||||||
| c.2049C>G | I683M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I683M variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of definitive predictions (five pathogenic vs. three benign) point to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.200174 | Structured | 0.143268 | Uncertain | 0.848 | 0.314 | 0.000 | -9.010 | Likely Pathogenic | 0.424 | Ambiguous | Likely Benign | 0.69 | Ambiguous | 0.1 | 0.68 | Ambiguous | 0.69 | Ambiguous | 0.74 | Ambiguous | 0.296 | Likely Benign | -2.88 | Deleterious | 0.999 | Probably Damaging | 0.986 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.0933 | 0.2662 | 2 | 1 | -2.6 | 18.03 | ||||||||||||||||||||||||||||||
| c.2050G>A | D684N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684N is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, and FATHMM, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM‑Consensus also reports it as likely pathogenic, and the Foldetta stability analysis is inconclusive. Protein‑stability predictors FoldX and Rosetta likewise return uncertain results. Overall, the preponderance of evidence points to a pathogenic effect, which contradicts the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | Uncertain | 1 | -13.155 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 1.47 | Ambiguous | 0.8 | 1.76 | Ambiguous | 1.62 | Ambiguous | 0.37 | Likely Benign | 0.382 | Likely Benign | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.746 | Possibly Damaging | 3.39 | Benign | 0.01 | Affected | 0.1157 | 0.6373 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||
| c.2051A>C | D684A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely converge on a deleterious effect: pathogenic calls are made by REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while only premPS and FATHMM predict a benign outcome. High‑accuracy assessments reinforce the pathogenic interpretation: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No evidence is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.34 | Destabilizing | 1.1 | 2.85 | Destabilizing | 3.10 | Destabilizing | 0.28 | Likely Benign | 0.547 | Likely Pathogenic | -7.98 | Deleterious | 0.994 | Probably Damaging | 0.758 | Possibly Damaging | 3.42 | Benign | 0.01 | Affected | 0.3477 | 0.5423 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.2051A>G | D684G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684G is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess the variant’s effect largely agree on a deleterious outcome. Benign predictions come from premPS and FATHMM, whereas the remaining 12 tools—including REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify it as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports pathogenic. No prediction is inconclusive or missing. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -14.238 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.34 | Destabilizing | 1.0 | 4.07 | Destabilizing | 3.71 | Destabilizing | -0.30 | Likely Benign | 0.561 | Likely Pathogenic | -6.98 | Deleterious | 0.999 | Probably Damaging | 0.935 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.3686 | 0.5403 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.2052C>A | D684E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D684E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, a majority of predictors (SGM‑Consensus, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; predictions from Rosetta and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -9.506 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.18 | Destabilizing | 0.66 | Ambiguous | 0.362 | Likely Benign | -3.99 | Deleterious | 0.910 | Possibly Damaging | 0.210 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1316 | 0.6187 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2052C>G | D684E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684E is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of algorithms predict a deleterious effect: FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Two methods (Rosetta and premPS) returned uncertain results. High‑accuracy assessments further support a damaging impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Overall, the computational evidence overwhelmingly indicates that D684E is pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -9.506 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.18 | Destabilizing | 0.66 | Ambiguous | 0.362 | Likely Benign | -3.99 | Deleterious | 0.910 | Possibly Damaging | 0.210 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1316 | 0.6187 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2053T>A | L685M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685M is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. Uncertain predictions come from premPS, Foldetta, Rosetta, and AlphaMissense‑Optimized. High‑accuracy methods give inconclusive results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑to‑2 tie and therefore uncertain; Foldetta also reports an uncertain stability change. Consequently, the overall computational evidence is mixed, with a slight tilt toward pathogenicity. Thus, the variant is most likely pathogenic based on predictions, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -10.790 | Likely Pathogenic | 0.902 | Likely Pathogenic | Ambiguous | 0.35 | Likely Benign | 0.1 | 1.01 | Ambiguous | 0.68 | Ambiguous | 0.83 | Ambiguous | 0.281 | Likely Benign | -2.00 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.29 | Benign | 0.01 | Affected | 0.0814 | 0.2758 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2054T>C | L685S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.303 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.08 | Destabilizing | 0.2 | 2.95 | Destabilizing | 3.02 | Destabilizing | 1.24 | Destabilizing | 0.520 | Likely Pathogenic | -5.99 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.27 | Benign | 0.01 | Affected | 0.2844 | 0.0505 | -3 | -2 | -4.6 | -26.08 | |||||||||||||||||||||||||||||
| c.2055G>C | L685F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685F is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the change as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX and Rosetta predictions are uncertain and are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic impact for the variant, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.304 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.62 | Ambiguous | 0.2 | 1.80 | Ambiguous | 1.71 | Ambiguous | 0.50 | Likely Benign | 0.300 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.33 | Benign | 0.01 | Affected | 0.0724 | 0.2367 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2055G>T | L685F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L685F is not reported in ClinVar and has no gnomAD entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, and FATHMM, whereas pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized classifies the change as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, while Foldetta’s stability analysis is inconclusive. FoldX and Rosetta predictions are uncertain and are treated as unavailable. Overall, the preponderance of evidence points to a pathogenic impact for the variant, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.175930 | Structured | 0.162061 | Uncertain | 0.913 | 0.280 | 0.000 | -12.304 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 1.62 | Ambiguous | 0.2 | 1.80 | Ambiguous | 1.71 | Ambiguous | 0.50 | Likely Benign | 0.300 | Likely Benign | -3.99 | Deleterious | 0.999 | Probably Damaging | 0.895 | Possibly Damaging | 3.33 | Benign | 0.01 | Affected | 0.0724 | 0.2367 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||
| c.2057G>T | G686V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686V has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on benign impact are Rosetta and FATHMM, while the majority of other in silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus score (Likely Pathogenic) indicate a pathogenic effect. Uncertain results come from FoldX, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for G686V, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -13.751 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.89 | Ambiguous | 0.5 | 0.21 | Likely Benign | 0.55 | Ambiguous | 0.74 | Ambiguous | 0.570 | Likely Pathogenic | -8.08 | Deleterious | 1.000 | Probably Damaging | 0.979 | Probably Damaging | 3.31 | Benign | 0.01 | Affected | 0.1059 | 0.3646 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||
| c.2059C>G | R687G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R687G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM, whereas the remaining tools (SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta indicates a destabilizing, pathogenic effect. AlphaMissense‑Optimized is uncertain and therefore treated as unavailable. Overall, the variant is most likely pathogenic based on the consensus of predictive tools, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | -12.900 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 2.94 | Destabilizing | 0.3 | 2.53 | Destabilizing | 2.74 | Destabilizing | 1.27 | Destabilizing | 0.360 | Likely Benign | -6.26 | Deleterious | 1.000 | Probably Damaging | 0.990 | Probably Damaging | 3.88 | Benign | 0.01 | Affected | 0.2508 | 0.2119 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.2060G>C | R687P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R687P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the sole benign predictor, whereas the remaining eleven tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also indicates pathogenicity. With the overwhelming majority of evidence pointing to a damaging effect and no conflicting ClinVar annotation, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.054297 | Structured | 0.191060 | Uncertain | 0.914 | 0.259 | 0.000 | -15.697 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.31 | Destabilizing | 0.3 | 6.63 | Destabilizing | 4.47 | Destabilizing | 0.89 | Ambiguous | 0.553 | Likely Pathogenic | -6.12 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 3.87 | Benign | 0.01 | Affected | 0.1811 | 0.3159 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.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.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.2068T>A | S690T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and polyPhen‑2 HumVar, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive (FoldX, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -11.380 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.39 | Likely Benign | 0.67 | Ambiguous | 0.311 | Likely Benign | -2.84 | Deleterious | 0.943 | Possibly Damaging | 0.267 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1059 | 0.4674 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2068T>C | S690P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, a conclusion that does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | Uncertain | 1 | -14.568 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.3 | 4.40 | Destabilizing | 4.62 | Destabilizing | 1.42 | Destabilizing | 0.431 | Likely Benign | -4.77 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.44 | Benign | 0.01 | Affected | 3.42 | 17 | 0.1787 | 0.4050 | 1 | -1 | -0.8 | 10.04 | 207.5 | 15.1 | 0.1 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl side chain of Ser690, located in an α-helix (res. Leu696-Leu685), forms a hydrogen bond with the backbone carbonyl group of Ser410 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399). In the variant simulations, the pyrrolidine side chain of Pro690 cannot form hydrogen bonds with the C2 domain residue, resulting in the loss of this inter-domain connection. Additionally, prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Gly686, introducing a slight bend in the α-helix and compromising its integrity. | |||||||||||||||
| c.2074C>A | L692M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2) and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Thus, the overall evidence slightly favors pathogenicity, with a majority of standard tools predicting a deleterious impact. The variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -9.659 | Likely Pathogenic | 0.746 | Likely Pathogenic | Likely Benign | 0.49 | Likely Benign | 0.0 | 1.81 | Ambiguous | 1.15 | Ambiguous | 1.01 | Destabilizing | 0.302 | Likely Benign | -1.99 | Neutral | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.07 | Benign | 0.01 | Affected | 0.0754 | 0.2585 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.2074C>G | L692V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized indicates benign, but the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves as pathogenic, and Foldetta also predicts pathogenic. No predictions are missing or inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for the variant, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | -11.441 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 3.29 | Destabilizing | 0.1 | 2.91 | Destabilizing | 3.10 | Destabilizing | 1.57 | Destabilizing | 0.286 | Likely Benign | -2.99 | Deleterious | 0.978 | Probably Damaging | 0.606 | Possibly Damaging | 3.12 | Benign | 0.01 | Affected | 0.1395 | 0.2460 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.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.2077C>G | H693D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693D is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a pathogenic effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -15.500 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.60 | Destabilizing | 0.1 | 2.03 | Destabilizing | 2.32 | Destabilizing | 1.62 | Destabilizing | 0.578 | Likely Pathogenic | -8.97 | Deleterious | 1.000 | Probably Damaging | 0.991 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.2166 | 0.1108 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.2078A>C | H693P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect are limited to FATHMM, which classifies the variant as benign. All other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic or likely pathogenic impact. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -16.281 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 5.54 | Destabilizing | 0.2 | 6.09 | Destabilizing | 5.82 | Destabilizing | 1.06 | Destabilizing | 0.600 | Likely Pathogenic | -9.97 | Deleterious | 1.000 | Probably Damaging | 0.996 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.2080 | 0.3210 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||
| c.2078A>G | H693R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, while the majority of algorithms (SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; FoldX, Rosetta, and Foldetta are inconclusive. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect, and Foldetta’s stability analysis is unavailable. 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 annotation (none is present). 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 | -14.326 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.39 | Ambiguous | 0.2 | 1.28 | Ambiguous | 1.34 | Ambiguous | 1.03 | Destabilizing | 0.593 | Likely Pathogenic | -7.97 | Deleterious | 0.998 | Probably Damaging | 0.646 | Possibly Damaging | 3.13 | Benign | 0.01 | Affected | 0.1839 | 0.1670 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.2078A>T | H693L 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant H693L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from Foldetta, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain results are reported by FoldX and Rosetta. High‑accuracy assessments indicate AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also leans pathogenic, whereas Foldetta predicts benign stability. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.073402 | Structured | 0.323991 | Uncertain | 0.964 | 0.260 | 0.000 | -14.006 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | -0.53 | Ambiguous | 0.1 | 0.92 | Ambiguous | 0.20 | Likely Benign | -0.29 | Likely Benign | 0.573 | Likely Pathogenic | -10.96 | Deleterious | 0.979 | Probably Damaging | 0.390 | Benign | 3.18 | Benign | 0.01 | Affected | 0.0824 | 0.4675 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.2079T>A | H693Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FATHMM, while the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict pathogenicity. FoldX and Rosetta give uncertain stability changes, and Foldetta likewise reports no definitive effect. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence from multiple pathogenic‑oriented predictors and the high‑accuracy consensus indicates that H693Q is most likely pathogenic, a conclusion that aligns with the lack of ClinVar annotation and gnomAD data. 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 | -11.425 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.85 | Ambiguous | 1.27 | Destabilizing | 0.386 | Likely Benign | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.921 | Probably Damaging | 3.14 | Benign | 0.01 | Affected | 0.1274 | 0.2955 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.2079T>G | H693Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H693Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and FATHMM, while the remaining evaluated algorithms (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) all predict pathogenicity. FoldX and Rosetta give uncertain stability changes, and Foldetta likewise reports no definitive effect. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence from multiple pathogenic‑oriented predictors and the high‑accuracy consensus indicates that H693Q is most likely pathogenic, a conclusion that aligns with the lack of ClinVar annotation and gnomAD data. 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 | -11.425 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.92 | Ambiguous | 0.1 | 0.78 | Ambiguous | 0.85 | Ambiguous | 1.27 | Destabilizing | 0.386 | Likely Benign | -7.97 | Deleterious | 1.000 | Probably Damaging | 0.921 | Probably Damaging | 3.14 | Benign | 0.01 | Affected | 0.1274 | 0.2955 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| 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.2092G>C | E698Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E698Q is not reported in ClinVar and has no entries in gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No prediction or folding stability result is missing or inconclusive. Overall, the evidence is split, with an equal number of benign and pathogenic calls; the high‑accuracy tools lean toward benign but are not definitive. Thus, the variant’s pathogenicity remains uncertain and 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 | 0.120615 | Structured | 0.417514 | Uncertain | 0.922 | 0.315 | 0.000 | -8.369 | Likely Pathogenic | 0.714 | Likely Pathogenic | Likely Benign | 0.00 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.18 | Likely Benign | -0.02 | Likely Benign | 0.326 | Likely Benign | -2.86 | Deleterious | 0.987 | Probably Damaging | 0.946 | Probably Damaging | 3.35 | Benign | 0.01 | Affected | 0.1029 | 0.3702 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| 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.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.2096T>G | V699G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V699G has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FATHMM and AlphaMissense‑Optimized, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b) uniformly predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta also predicts pathogenic. Consequently, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.069024 | Structured | 0.432975 | Uncertain | 0.935 | 0.315 | 0.000 | -11.912 | Likely Pathogenic | 0.481 | Ambiguous | Likely Benign | 2.22 | Destabilizing | 0.0 | 3.25 | Destabilizing | 2.74 | Destabilizing | 1.77 | Destabilizing | 0.514 | Likely Pathogenic | -5.11 | Deleterious | 0.972 | Probably Damaging | 0.999 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.1830 | 0.2240 | -1 | -3 | -4.6 | -42.08 | ||||||||||||||||||||||||||||||
| c.2099T>A | L700Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates a benign change, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. No predictions are missing or inconclusive. Overall, the preponderance of evidence from the majority of tools points to a pathogenic effect, 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 | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -10.522 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 2.41 | Destabilizing | 0.1 | 4.02 | Destabilizing | 3.22 | Destabilizing | 1.35 | Destabilizing | 0.321 | Likely Benign | -3.79 | Deleterious | 0.994 | Probably Damaging | 0.896 | Possibly Damaging | 3.34 | Benign | 0.01 | Affected | 0.1074 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2099T>C | L700P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while only FATHMM predicts it benign. The SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Pathogenic” verdict (3 pathogenic vs. 1 benign). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -13.092 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 7.29 | Destabilizing | 0.5 | 12.85 | Destabilizing | 10.07 | Destabilizing | 1.84 | Destabilizing | 0.541 | Likely Pathogenic | -4.31 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 3.30 | Benign | 0.01 | Affected | 0.3603 | 0.1025 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||
| 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.2110A>T | S704C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704C is not 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. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments give a mixed picture: 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) is uncertain. Other stability‑based tools such as FoldX, Rosetta, and premPS also return uncertain results. Overall, the majority of individual predictors lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Thus, 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. | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | -10.438 | Likely Pathogenic | 0.423 | Ambiguous | Likely Benign | 1.56 | Ambiguous | 0.1 | 0.98 | Ambiguous | 1.27 | Ambiguous | 0.52 | Ambiguous | 0.251 | Likely Benign | -3.52 | Deleterious | 0.997 | Probably Damaging | 0.789 | Possibly Damaging | 3.40 | Benign | 0.01 | Affected | 0.0789 | 0.4612 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||
| c.2120C>G | A707G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A707G missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) give uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign, while Foldetta remains uncertain. Overall, the majority of definitive predictions lean toward a benign effect, and there is no ClinVar status 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. | GAP | 0.203355 | Structured | 0.371229 | Uncertain | 0.927 | 0.365 | 0.000 | -7.480 | In-Between | 0.224 | Likely Benign | Likely Benign | 1.45 | Ambiguous | 0.0 | 1.52 | Ambiguous | 1.49 | Ambiguous | 0.62 | Ambiguous | 0.198 | Likely Benign | -2.60 | Deleterious | 0.991 | Probably Damaging | 0.960 | Probably Damaging | 3.42 | Benign | 0.01 | Affected | 0.1678 | 0.2388 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.2128A>C | K710Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K710Q missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. The high‑accuracy AlphaMissense‑Optimized score classifies the variant as benign, whereas the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (uncertain), ESM1b (pathogenic), FATHMM (benign), and PROVEAN (pathogenic)—indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. 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. | GAP | 0.321458 | Structured | 0.370438 | Uncertain | 0.949 | 0.368 | 0.000 | -8.920 | Likely Pathogenic | 0.372 | Ambiguous | Likely Benign | 0.12 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.07 | Likely Benign | 0.49 | Likely Benign | 0.183 | Likely Benign | -3.58 | Deleterious | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.3043 | 0.1214 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||
| 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.2143C>A | P715T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus. Two tools, Foldetta and premPS, returned uncertain results. High‑accuracy analyses further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenicity; Foldetta remains inconclusive. Overall, the majority of evidence points toward 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 | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -10.501 | Likely Pathogenic | 0.744 | Likely Pathogenic | Likely Benign | 2.55 | Destabilizing | 0.1 | 0.29 | Likely Benign | 1.42 | Ambiguous | 0.72 | Ambiguous | 0.368 | Likely Benign | -7.23 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.37 | Benign | 0.01 | Affected | 0.1357 | 0.4072 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||
| c.2143C>T | P715S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant P715S is listed in ClinVar as pathogenic (ClinVar ID 1804065.0) and is present in gnomAD (ID 6‑33441608‑C‑T). Functional prediction tools that agree on a benign effect are REVEL and FATHMM. Those that predict a pathogenic effect include FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. Predictions that are inconclusive are Rosetta, premPS, ESM1b, 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 majority of evidence points to a pathogenic 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. | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | Likely Pathogenic | 1 | 6-33441608-C-T | 1 | 6.20e-7 | -7.635 | In-Between | 0.787 | Likely Pathogenic | Ambiguous | 3.54 | Destabilizing | 0.0 | 0.81 | Ambiguous | 2.18 | Destabilizing | 0.94 | Ambiguous | 0.277 | Likely Benign | -7.17 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.43 | Benign | 0.01 | Affected | 3.50 | 9 | 0.2977 | 0.3755 | 1 | -1 | 0.8 | -10.04 | 231.8 | -14.0 | -0.1 | 0.0 | -0.8 | 0.1 | X | Uncertain | Pro715, along with Gly712 and Pro713, are located in a hinge region of an α-helix making a ~90-degree turn (res. Lys705-Leu725). In the WT simulations, the pyrrolidine side chain of Pro715, lacking the backbone amide groups altogether, forces the tight helix turn to take place while also hydrophobically packing with nearby residues (e.g., Leu700, Leu708, Leu714, and Leu718). Leu715, with a normal amide backbone, could potentially affect protein folding and turn formation, although this was not observed in the variant simulations. Additionally, the hydroxyl group of the Ser715 side chain can form hydrogen bonds with the backbone carbonyl group of Gly712 and disrupt the hydrophobic packing arrangement of the leucine residues from the neighboring α-helices, impacting the GAP domain tertiary assembly. | ||||||||||||||
| c.2144C>G | P715R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715R 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 (SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts a likely pathogenic outcome, AlphaMissense‑Optimized is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Because the pathogenic predictions outnumber the benign ones and the high‑accuracy consensus supports a deleterious effect, the variant is most likely pathogenic. This assessment does not contradict ClinVar, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -12.191 | Likely Pathogenic | 0.940 | Likely Pathogenic | Ambiguous | 2.19 | Destabilizing | 0.1 | 0.53 | Ambiguous | 1.36 | Ambiguous | 0.87 | Ambiguous | 0.324 | Likely Benign | -8.09 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.53 | Benign | 0.01 | Affected | 0.1389 | 0.2620 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.2144C>T | P715L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P715L is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, Rosetta, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. FoldX and premPS give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as uncertain. Because the majority of consensus and individual predictors indicate pathogenicity, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for P715L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.243554 | Structured | 0.409757 | Uncertain | 0.956 | 0.362 | 0.000 | -12.207 | Likely Pathogenic | 0.764 | Likely Pathogenic | Likely Benign | 1.43 | Ambiguous | 0.1 | 0.06 | Likely Benign | 0.75 | Ambiguous | 0.58 | Ambiguous | 0.318 | Likely Benign | -9.10 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.39 | Benign | 0.01 | Affected | 0.1944 | 0.5105 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||
| c.2146C>G | R716G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R716G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas a majority of tools predict a pathogenic impact: 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, is classified 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. Other stability predictors (FoldX, Rosetta, premPS) are also Uncertain. Overall, the balance of evidence from the majority of tools and the SGM‑Consensus indicates a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.419135 | Uncertain | 0.962 | 0.379 | 0.000 | -9.927 | Likely Pathogenic | 0.728 | Likely Pathogenic | Likely Benign | 1.32 | Ambiguous | 0.1 | 1.63 | Ambiguous | 1.48 | Ambiguous | 0.72 | Ambiguous | 0.359 | Likely Benign | -5.70 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.36 | Benign | 0.01 | Affected | 0.3437 | 0.2466 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.2147G>C | R716P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R716P 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, FoldX, premPS, and FATHMM; pathogenic predictions come from AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, Rosetta, Foldetta, and the SGM‑Consensus score. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.419135 | Uncertain | 0.962 | 0.379 | 0.000 | -10.744 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.18 | Likely Benign | 0.1 | 5.67 | Destabilizing | 2.93 | Destabilizing | 0.49 | Likely Benign | 0.320 | Likely Benign | -5.75 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.33 | Benign | 0.01 | Affected | 0.2140 | 0.3576 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.2147G>T | R716L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R716L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, premPS, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 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 likely pathogenic, and Foldetta as benign. Overall, the majority of predictions (7/13) lean toward pathogenicity, with a near‑even split and a slight edge for pathogenic. The variant is therefore most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists for R716L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.419135 | Uncertain | 0.962 | 0.379 | 0.000 | -10.690 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.31 | Likely Benign | 0.0 | 0.51 | Ambiguous | 0.41 | Likely Benign | 0.37 | Likely Benign | 0.289 | Likely Benign | -5.70 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.46 | Benign | 0.01 | Affected | 0.1701 | 0.3775 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.2158G>A | D720N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D720N is listed in ClinVar as benign (ClinVar ID 2837618.0) and is present in gnomAD (ID 6‑33441623‑G‑A). Prediction tools that indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus as pathogenic. With seven pathogenic versus six benign predictions overall, the variant is most likely pathogenic according to in‑silico evidence, which contradicts the benign classification in ClinVar. 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 | Likely Benign | 1 | 6-33441623-G-A | 5 | 3.10e-6 | -9.135 | Likely Pathogenic | 0.654 | Likely Pathogenic | Likely Benign | 0.01 | Likely Benign | 0.0 | -0.20 | Likely Benign | -0.10 | Likely Benign | 0.46 | Likely Benign | 0.289 | Likely Benign | -3.74 | Deleterious | 1.000 | Probably Damaging | 0.995 | Probably Damaging | 2.18 | Pathogenic | 0.01 | Affected | 3.50 | 9 | 0.1216 | 0.5513 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||
| 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.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.2170G>A | A724T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A724T missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that indicate a benign effect include REVEL, premPS, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Predictions that are inconclusive are AlphaMissense‑Default, FoldX, Rosetta, and Foldetta. 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 as uncertain. Overall, the majority of evaluated tools (seven pathogenic vs. three benign) suggest a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, as there is no existing classification to contradict. 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 | 0.476583 | Structured | 0.458050 | Uncertain | 0.923 | 0.483 | 0.250 | -8.047 | Likely Pathogenic | 0.456 | Ambiguous | Likely Benign | 0.95 | Ambiguous | 0.1 | 1.10 | Ambiguous | 1.03 | Ambiguous | 0.40 | Likely Benign | 0.273 | Likely Benign | -2.87 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | 2.09 | Pathogenic | 0.01 | Affected | 0.1149 | 0.5897 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.2171C>T | A724V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A724V missense variant 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, Foldetta, premPS, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by 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, classifies the variant as likely pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, SGM Consensus predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. With no ClinVar annotation, there is no contradiction between the predictions and existing clinical data. Overall, the evidence is mixed, but the majority of high‑confidence tools lean toward a benign effect, suggesting the variant is most likely benign rather than pathogenic. 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 | -9.000 | Likely Pathogenic | 0.471 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.1 | 0.35 | Likely Benign | 0.39 | Likely Benign | 0.24 | Likely Benign | 0.241 | Likely Benign | -3.28 | Deleterious | 0.999 | Probably Damaging | 0.988 | Probably Damaging | 2.07 | Pathogenic | 0.01 | Affected | 0.0872 | 0.5620 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.2173C>G | L725V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and AlphaMissense‑Optimized, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. The remaining methods (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) are inconclusive. 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 provides no definitive stability change. Overall, the majority of evidence points toward 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 | 0.557691 | Disordered | 0.455613 | Uncertain | 0.911 | 0.491 | 0.625 | -8.291 | Likely Pathogenic | 0.461 | Ambiguous | Likely Benign | 1.76 | Ambiguous | 0.1 | 1.87 | Ambiguous | 1.82 | Ambiguous | 0.77 | Ambiguous | 0.183 | Likely Benign | -2.69 | Deleterious | 0.993 | Probably Damaging | 0.992 | Probably Damaging | 1.36 | Pathogenic | 0.01 | Affected | 0.1739 | 0.3977 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.2176A>T | R726W 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R726W has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a split: benign calls from REVEL, FoldX, Rosetta, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized, while pathogenic calls come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further reveal AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of tools (seven) predict a benign effect, but the SGM‑Consensus and several high‑accuracy methods indicate pathogenicity, leaving the variant’s clinical significance uncertain. The predictions do 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 | 0.521092 | Disordered | 0.449098 | Uncertain | 0.888 | 0.513 | 0.625 | -10.091 | Likely Pathogenic | 0.580 | Likely Pathogenic | Likely Benign | 0.46 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.46 | Likely Benign | 0.15 | Likely Benign | 0.217 | Likely Benign | -3.72 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | 2.57 | Benign | 0.01 | Affected | 0.1161 | 0.4252 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||
| c.2194A>T | R732W 2D AIThe SynGAP1 missense variant R732W 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while 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, five tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict these computational findings. Thus, the variant is most likely pathogenic based on the current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -11.976 | Likely Pathogenic | 0.252 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -3.57 | Deleterious | 1.000 | Probably Damaging | 0.973 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | 0.1332 | 0.2748 | 2 | -3 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2195G>T | R732M 2D AIThe SynGAP1 missense variant R732M 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, 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, and PROVEAN) also favors a benign outcome. Foldetta results are unavailable. Overall, the balance of evidence (5 benign vs 3 pathogenic predictions) indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.846163 | Disordered | 0.412403 | Uncertain | 0.427 | 0.673 | 0.750 | -9.956 | Likely Pathogenic | 0.414 | Ambiguous | Likely Benign | 0.098 | Likely Benign | -1.42 | Neutral | 0.840 | Possibly Damaging | 0.357 | Benign | 2.55 | Benign | 0.01 | Affected | 0.1432 | 0.2980 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2212A>C | S738R 2D AIThe SynGAP1 missense variant S738R 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, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S738R, 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 | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -4.241 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.066 | Likely Benign | -1.55 | Neutral | 0.473 | Possibly Damaging | 0.193 | Benign | 2.69 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0887 | 0.2891 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2212A>G | S738G 2D AIThe SynGAP1 missense variant S738G 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, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are unavailable. 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 | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -3.863 | Likely Benign | 0.053 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -1.53 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.66 | Benign | 0.01 | Affected | 0.2032 | 0.3385 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.2212A>T | S738C 2D AIThe SynGAP1 missense variant S738C is reported in ClinVar as not yet classified and is present in gnomAD (variant ID 6‑33441677‑A‑T). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict pathogenic. High‑accuracy methods give a benign result from AlphaMissense‑Optimized and a likely benign consensus from SGM‑Consensus; Foldetta predictions are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | 6-33441677-A-T | 4 | 2.48e-6 | -6.373 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -2.09 | Neutral | 0.975 | Probably Damaging | 0.815 | Possibly Damaging | 2.63 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1112 | 0.3982 | -1 | 0 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||
| c.2213G>T | S738I 2D AIThe SynGAP1 missense variant S738I 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -4.312 | Likely Benign | 0.113 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.78 | Neutral | 0.642 | Possibly Damaging | 0.393 | Benign | 2.66 | Benign | 0.01 | Affected | 0.0847 | 0.3636 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2214T>A | S738R 2D AIThe SynGAP1 missense variant S738R 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, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus (majority vote) as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -4.241 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.068 | Likely Benign | -1.55 | Neutral | 0.473 | Possibly Damaging | 0.193 | Benign | 2.69 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0887 | 0.2891 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.2214T>G | S738R 2D AIThe SynGAP1 missense variant S738R is listed in ClinVar (ID 1592652.0) as Benign and is present in gnomAD (variant ID 6‑33441679‑T‑G). 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, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Benign; Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar designation and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | Benign | 1 | 6-33441679-T-G | 1 | 6.20e-7 | -4.241 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.068 | Likely Benign | -1.55 | Neutral | 0.473 | Possibly Damaging | 0.193 | Benign | 2.69 | Benign | 0.01 | Affected | 4.32 | 2 | 0.0887 | 0.2891 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||
| c.2218C>T | R740W 2D AIThe SynGAP1 missense variant R740W is listed in ClinVar with an uncertain significance and is present in the gnomAD database (ID 6‑33441683‑C‑T). Prediction tools that classify the variant as benign include REVEL, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicting a benign effect; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two benign vs. two pathogenic calls) and is treated as unavailable, and no Foldetta stability data are reported. Overall, the majority of conventional tools (five pathogenic vs. four benign) suggest a pathogenic impact, whereas the single high‑accuracy tool indicates benign. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict the ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.771762 | Disordered | 0.475392 | Uncertain | 0.269 | 0.849 | 0.875 | Uncertain | 2 | 6-33441683-C-T | 6 | 3.72e-6 | -8.561 | Likely Pathogenic | 0.168 | Likely Benign | Likely Benign | 0.180 | Likely Benign | -3.09 | Deleterious | 1.000 | Probably Damaging | 0.938 | Probably Damaging | 2.52 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1566 | 0.3375 | 2 | -3 | 3.6 | 30.03 | |||||||||||||||||||||||||||||||||
| c.2222C>A | P741H 2D AIThe SynGAP1 missense variant P741H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The prediction 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 Benign | 0.885302 | Disordered | 0.493550 | Uncertain | 0.354 | 0.859 | 0.875 | -5.592 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.099 | Likely Benign | -0.99 | Neutral | 0.006 | Benign | 0.007 | Benign | 2.81 | Benign | 0.01 | Affected | 0.1372 | 0.3831 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2224C>T | R742W 2D AIThe SynGAP1 missense variant R742W is listed in ClinVar (ID 2581888.0) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33441689‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors 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 points to a benign impact, which is consistent with the ClinVar “Uncertain” classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.509587 | Binding | 0.309 | 0.856 | 0.875 | Uncertain | 1 | 6-33441689-C-T | 6 | 3.72e-6 | -7.725 | In-Between | 0.133 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -1.71 | Neutral | 0.992 | Probably Damaging | 0.684 | Possibly Damaging | 2.66 | Benign | 0.01 | Affected | 4.32 | 2 | 0.1638 | 0.2839 | -3 | 2 | 3.6 | 30.03 | ||||||||||||||||||||||||||||||||
| c.2228C>A | P743H 2D AIThe SynGAP1 missense variant P743H 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, so it does not influence the overall assessment. Overall, the majority of computational evidence points to a benign effect for P743H, 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 | 0.852992 | Disordered | 0.526809 | Binding | 0.317 | 0.862 | 0.875 | -5.649 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.99 | Neutral | 0.989 | Probably Damaging | 0.870 | Possibly Damaging | 2.70 | Benign | 0.01 | Affected | 0.1653 | 0.3762 | 0 | -2 | -1.6 | 40.02 | |||||||||||||||||||||||||||||||||||||||
| c.2232G>C | Q744H 2D AIThe SynGAP1 missense variant Q744H 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‑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 result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q744H, 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -4.359 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.83 | Neutral | 0.975 | Probably Damaging | 0.574 | Possibly Damaging | 2.68 | Benign | 0.01 | Affected | 0.1452 | 0.3443 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2232G>T | Q744H 2D AIThe SynGAP1 missense variant Q744H 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‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: 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 Q744H, 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 | 0.852992 | Disordered | 0.540428 | Binding | 0.316 | 0.866 | 0.875 | -4.359 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.83 | Neutral | 0.975 | Probably Damaging | 0.574 | Possibly Damaging | 2.68 | Benign | 0.01 | Affected | 0.1452 | 0.3443 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2234C>G | P745R 2D AIThe SynGAP1 missense variant P745R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. 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 predicts Benign, and the SGM‑Consensus also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the conclusion. Overall, the majority of computational evidence points to a benign effect for P745R, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -4.564 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.245 | Likely Benign | -2.90 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.51 | Benign | 0.01 | Affected | 0.1571 | 0.2852 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2234C>T | P745L 2D AIThe SynGAP1 missense variant P745L 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, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus (majority vote) as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.558331 | Binding | 0.341 | 0.860 | 0.875 | -6.303 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.211 | Likely Benign | -3.79 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.53 | Benign | 0.01 | Affected | 0.2205 | 0.5188 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2243T>A | L748Q 2D AIThe SynGAP1 missense variant L748Q 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 (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for L748Q, 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 | 0.703578 | Disordered | 0.611637 | Binding | 0.339 | 0.863 | 0.750 | -3.177 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.46 | Neutral | 0.912 | Possibly Damaging | 0.611 | Possibly Damaging | 2.74 | Benign | 0.01 | Affected | 0.1235 | 0.1246 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2246G>T | R749L 2D AIThe SynGAP1 missense variant R749L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictors that are available—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign classification. Consequently, the overall evidence points to the variant being most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.626050 | Binding | 0.337 | 0.860 | 0.625 | -3.926 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -2.15 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.2106 | 0.5154 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||||||||||||
| c.2249G>A | G750E 2D AISynGAP1 missense variant G750E is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta results are unavailable. Overall, the majority of evidence points to 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. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | Uncertain | 1 | -2.618 | Likely Benign | 0.413 | Ambiguous | Likely Benign | 0.146 | Likely Benign | -2.27 | Neutral | 1.000 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.01 | Affected | 3.99 | 5 | 0.1326 | 0.3768 | 0 | -2 | -3.1 | 72.06 | ||||||||||||||||||||||||||||||||||||
| c.2249G>T | G750V 2D AIThe SynGAP1 missense variant G750V is not 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 (2 benign vs 2 pathogenic votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore show AlphaMissense‑Optimized as benign, while the remaining high‑confidence tools (PROVEAN, polyPhen‑2, SIFT, FATHMM) all indicate pathogenicity. Overall, the majority of evidence (five pathogenic vs four benign) points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -4.512 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -2.54 | Deleterious | 0.984 | Probably Damaging | 0.850 | Possibly Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.1270 | 0.4212 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||||
| c.2255C>T | S752L 2D AIThe SynGAP1 missense variant S752L is listed in ClinVar with an “Uncertain” status (ClinVar ID 2143952.0) and is present in gnomAD (ID 6‑33441720‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | Uncertain | 2 | 6-33441720-C-T | 6 | 3.72e-6 | -3.386 | Likely Benign | 0.182 | Likely Benign | Likely Benign | 0.195 | Likely Benign | -2.09 | Neutral | 0.993 | Probably Damaging | 0.641 | Possibly Damaging | 1.51 | Pathogenic | 0.01 | Affected | 3.99 | 5 | 0.1308 | 0.5909 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.2284G>T | D762Y 2D AIThe SynGAP1 D762Y 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 and ESM1b, whereas a larger group predicts a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic”; Foldetta (a protein‑folding stability approach combining FoldX‑MD and Rosetta) has no available output for this variant. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -6.959 | Likely Benign | 0.905 | Likely Pathogenic | Ambiguous | 0.219 | Likely Benign | -3.24 | Deleterious | 1.000 | Probably Damaging | 0.989 | Probably Damaging | 2.07 | Pathogenic | 0.01 | Affected | 0.0700 | 0.7929 | -4 | -3 | 2.2 | 48.09 | |||||||||||||||||||||||||||||||||||||||
| c.2285A>T | D762V 2D AIThe SynGAP1 D762V missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b. Tools that agree on a pathogenic effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returned an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of consensus tools predict a pathogenic impact, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -6.122 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.229 | Likely Benign | -1.98 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.08 | Pathogenic | 0.01 | Affected | 0.1105 | 0.8785 | -2 | -3 | 7.7 | -15.96 | ||||||||||||||||||||||||||||||||||||||||
| c.2290A>T | N764Y 2D AIThe SynGAP1 missense variant N764Y 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, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta data are unavailable. Overall, the balance of evidence favors a pathogenic interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.914 | Likely Benign | 0.680 | Likely Pathogenic | Likely Benign | 0.158 | Likely Benign | -2.85 | Deleterious | 0.998 | Probably Damaging | 0.967 | Probably Damaging | 2.58 | Benign | 0.01 | Affected | 0.0552 | 0.4175 | -2 | -2 | 2.2 | 49.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2296T>C | S766P 2D AIThe SynGAP1 missense variant S766P is reported in gnomAD (ID 6‑33442454‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while SIFT uniquely predicts it as pathogenic. The remaining 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, and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442454-T-C | 1 | 1.28e-6 | -7.343 | In-Between | 0.374 | Ambiguous | Likely Benign | 0.193 | Likely Benign | -0.91 | Neutral | 0.006 | Benign | 0.013 | Benign | 4.07 | Benign | 0.01 | Affected | 3.64 | 6 | 0.2216 | 0.5862 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.2309A>T | Q770L 2D AIThe SynGAP1 missense variant Q770L is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q770L, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -5.524 | Likely Benign | 0.521 | Ambiguous | Likely Benign | 0.197 | Likely Benign | -2.17 | Neutral | 0.095 | Benign | 0.030 | Benign | 4.14 | Benign | 0.01 | Affected | 0.0776 | 0.6230 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2310G>C | Q770H 2D AIThe SynGAP1 missense variant Q770H 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, as none exists for Q770H. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.241 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.962 | Probably Damaging | 0.515 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1579 | 0.4344 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2310G>T | Q770H 2D AIThe SynGAP1 missense variant Q770H 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 | 0.436924 | Structured | 0.923732 | Binding | 0.328 | 0.887 | 0.250 | -4.241 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.27 | Neutral | 0.962 | Probably Damaging | 0.515 | Possibly Damaging | 4.11 | Benign | 0.01 | Affected | 0.1579 | 0.4344 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.2326G>C | G776R 2D AIThe SynGAP1 missense variant G776R 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 tool returns an uncertain result, and the Foldetta protein‑folding stability assessment is unavailable for this variant. Overall, the balance of evidence leans toward a benign interpretation, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -6.209 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -2.28 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 4.22 | Benign | 0.01 | Affected | 0.0932 | 0.5115 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.2326G>T | G776C 2D AIThe SynGAP1 missense variant G776C is not reported in ClinVar but is present in gnomAD (ID 6‑33442484‑G‑T). Prediction tools cluster into benign (REVEL, FATHMM, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT). Two tools (ESM1b, AlphaMissense‑Default) return uncertain results. High‑accuracy assessments are limited: AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta data are unavailable. Overall, the majority of conventional predictors indicate pathogenicity, whereas the single high‑accuracy tool suggests benign. Given the preponderance of pathogenic predictions and the absence of a ClinVar entry, the variant is most likely pathogenic and does not contradict any existing ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | 6-33442484-G-T | -7.974 | In-Between | 0.380 | Ambiguous | Likely Benign | 0.181 | Likely Benign | -2.59 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 4.15 | Benign | 0.01 | Affected | 3.64 | 6 | 0.1235 | 0.4403 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||
| c.2327G>T | G776V 2D AIThe SynGAP1 missense variant G776V is listed in gnomAD (ID 6‑33442485‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also indicates a likely benign outcome; Foldetta data are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because none is reported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | 6-33442485-G-T | -6.541 | Likely Benign | 0.515 | Ambiguous | Likely Benign | 0.180 | Likely Benign | -2.25 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 4.19 | Benign | 0.01 | Affected | 3.64 | 6 | 0.0993 | 0.4223 | -3 | -1 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||
| c.2329C>T | L777F 2D AIThe SynGAP1 missense variant L777F 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 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 | 0.408655 | Structured | 0.876129 | Binding | 0.336 | 0.882 | 0.250 | -4.499 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -1.91 | Neutral | 0.968 | Probably Damaging | 0.966 | Probably Damaging | 3.98 | Benign | 0.01 | Affected | 0.0697 | 0.3576 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.2345A>C | D782A 2D AIThe SynGAP1 missense variant D782A 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 and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM‑Consensus, reports the variant as Likely Pathogenic, while AlphaMissense‑Optimized remains uncertain and Foldetta results are unavailable. Taken together, the preponderance of evidence from multiple in silico predictors and the SGM‑Consensus suggests that D782A is most likely pathogenic. 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 | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -7.054 | In-Between | 0.892 | Likely Pathogenic | Ambiguous | 0.345 | Likely Benign | -3.33 | Deleterious | 0.990 | Probably Damaging | 0.932 | Probably Damaging | 1.95 | Pathogenic | 0.01 | Affected | 0.3819 | 0.6121 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2346C>A | D782E 2D AIThe SynGAP1 missense variant D782E is not 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, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority (2 benign vs. 1 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 benign impact; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -4.447 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.75 | Neutral | 0.561 | Possibly Damaging | 0.207 | Benign | 2.14 | Pathogenic | 0.01 | Affected | 0.1351 | 0.7036 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2346C>G | D782E 2D AIThe SynGAP1 missense variant D782E is not 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, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a majority benign vote (2 benign vs. 1 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 benign impact; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -4.447 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.75 | Neutral | 0.561 | Possibly Damaging | 0.207 | Benign | 2.14 | Pathogenic | 0.01 | Affected | 0.1351 | 0.7036 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2348T>A | M783K 2D AIThe SynGAP1 missense variant M783K is not 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, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while 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 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. | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -4.923 | Likely Benign | 0.693 | Likely Pathogenic | Likely Benign | 0.206 | Likely Benign | -2.70 | Deleterious | 0.925 | Possibly Damaging | 0.424 | Benign | 2.66 | Benign | 0.01 | Affected | 0.1730 | 0.0912 | 0 | -1 | -5.8 | -3.02 | ||||||||||||||||||||||||||||||||||||||||
| c.2348T>G | M783R 2D AIThe SynGAP1 missense variant M783R is not 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), SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 benign vs 2 pathogenic). Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs four benign) lean toward a pathogenic impact. Thus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.736850 | Disordered | 0.738119 | Binding | 0.331 | 0.889 | 0.625 | -3.849 | Likely Benign | 0.655 | Likely Pathogenic | Likely Benign | 0.208 | Likely Benign | -2.69 | Deleterious | 0.925 | Possibly Damaging | 0.529 | Possibly Damaging | 2.66 | Benign | 0.01 | Affected | 0.1815 | 0.0893 | 0 | -1 | -6.4 | 24.99 | ||||||||||||||||||||||||||||||||||||||||
| c.2353C>A | R785S 2D AIThe SynGAP1 missense variant R785S is not reported in ClinVar and is absent from gnomAD. 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 the SGM‑Consensus score. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity, while the lack of a Foldetta result leaves that evidence inconclusive. Overall, the preponderance of pathogenic 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 | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | -2.926 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.157 | Likely Benign | -2.93 | Deleterious | 0.980 | Probably Damaging | 0.765 | Possibly Damaging | 2.34 | Pathogenic | 0.01 | Affected | 0.3523 | 0.3800 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2354G>A | R785H 2D AIThe SynGAP1 R785H missense variant (ClinVar ID 2321588.0) is listed as “Uncertain” in ClinVar and is present in gnomAD (ID 6‑33442906‑G‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, whereas the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a pathogenic outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, does not provide a result for this variant. Overall, the majority of computational predictions (five pathogenic versus three benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current predictions, and 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. | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | Uncertain | 2 | 6-33442906-G-A | 4 | 2.50e-6 | -4.782 | Likely Benign | 0.388 | Ambiguous | Likely Benign | 0.129 | Likely Benign | -2.61 | Deleterious | 0.999 | Probably Damaging | 0.947 | Probably Damaging | 2.25 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.3260 | 0.1589 | 2 | 0 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||
| c.2354G>C | R785P 2D AIThe SynGAP1 missense variant R785P is catalogued in gnomAD (6‑33442906‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from 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, reports the variant as Likely Pathogenic. High‑accuracy assessments further show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus remains Likely Pathogenic; Foldetta results are unavailable. Overall, the balance of evidence, with seven pathogenic versus three benign predictions and a pathogenic consensus from SGM, indicates that R785P is most likely pathogenic. This conclusion does not contradict ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | 6-33442906-G-C | -3.603 | Likely Benign | 0.721 | Likely Pathogenic | Likely Benign | 0.203 | Likely Benign | -4.12 | Deleterious | 0.998 | Probably Damaging | 0.958 | Probably Damaging | 2.24 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.2370 | 0.4485 | -2 | 0 | 2.9 | -59.07 | |||||||||||||||||||||||||||||||||||
| c.2354G>T | R785L 2D AIThe SynGAP1 missense variant R785L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta results are unavailable. Overall, the balance of evidence leans toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.859585 | Disordered | 0.681730 | Binding | 0.325 | 0.896 | 0.625 | -4.457 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.158 | Likely Benign | -4.43 | Deleterious | 0.960 | Probably Damaging | 0.627 | Possibly Damaging | 2.26 | Pathogenic | 0.01 | Affected | 0.1993 | 0.4539 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||
| c.2359C>A | P787T 2D AISynGAP1 missense variant P787T is listed in ClinVar as benign (ClinVar ID 862728.0) and is present in gnomAD (6‑33442911‑C‑A). Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions are made by AlphaMissense‑Default, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and the SGM‑Consensus score. The high‑accuracy AlphaMissense‑Optimized result is benign, whereas the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is 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 effect, which contradicts the ClinVar benign classification. Thus, the variant is most likely pathogenic, contradicting the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | Likely Benign | 1 | 6-33442911-C-A | 17 | 1.05e-5 | -4.813 | Likely Benign | 0.603 | Likely Pathogenic | Likely Benign | 0.258 | Likely Benign | -4.40 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.46 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.1577 | 0.5629 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||
| c.2360C>A | P787H 2D AIThe SynGAP1 missense variant P787H has no ClinVar entry and is not listed in gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic” (3 pathogenic votes versus 1 benign). High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of predictions lean toward pathogenicity, but this is contradicted by the benign call from AlphaMissense‑Optimized. Because ClinVar has no reported status, there is no conflict with existing clinical annotations. Thus, the variant is most likely pathogenic based on the prevailing computational evidence, though one high‑accuracy tool suggests a benign effect. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -5.819 | Likely Benign | 0.691 | Likely Pathogenic | Likely Benign | 0.308 | Likely Benign | -4.96 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.1790 | 0.4061 | 0 | -2 | -1.6 | 40.02 | ||||||||||||||||||||||||||||||||||||||
| c.2360C>T | P787L 2D AIThe SynGAP1 missense variant P787L is not reported in ClinVar (ClinVar status: not listed) and is absent from gnomAD (gnomAD ID: none). Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default—predict it to be pathogenic. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of predictions (seven pathogenic vs. three benign) lean toward pathogenicity, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.901269 | Disordered | 0.613211 | Binding | 0.377 | 0.899 | 0.750 | -3.924 | Likely Benign | 0.747 | Likely Pathogenic | Likely Benign | 0.256 | Likely Benign | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.2254 | 0.6034 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||
| c.2362T>C | S788P 2D AIThe SynGAP1 missense variant S788P is catalogued in gnomAD (ID 6‑33442914‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The AlphaMissense‑Default score is uncertain. A consensus derived from the SGM framework (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is unavailable for this residue. Taken together, the preponderance of evidence from standard predictors and the SGM consensus points to a likely pathogenic effect, which does not contradict any existing ClinVar annotation because none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | 6-33442914-T-C | -1.857 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.236 | Likely Benign | -3.91 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.51 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.2338 | 0.5537 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||
| c.2368A>C | T790P 2D AIThe SynGAP1 missense variant T790P has no ClinVar entry (ClinVar status: not reported) but is present in gnomAD (ID 6‑33442920‑A‑C). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, 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 majority of conventional tools (5 pathogenic vs 4 benign) lean toward a pathogenic interpretation, while the single high‑accuracy tool suggests benign. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this 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. | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | 6-33442920-A-C | -3.564 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.250 | Likely Benign | -3.55 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.25 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.2147 | 0.4748 | -1 | 0 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||||||||
| c.2369C>T | T790I 2D AIThe SynGAP1 missense variant T790I is not 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 predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. 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. | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | -3.556 | Likely Benign | 0.482 | Ambiguous | Likely Benign | 0.190 | Likely Benign | -3.08 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.28 | Pathogenic | 0.01 | Affected | 0.0987 | 0.5431 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2374G>A | E792K 2D AIThe SynGAP1 missense variant E792K 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, 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 also 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 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 | SH3-binding motif | 0.974374 | Disordered | 0.452261 | Uncertain | 0.352 | 0.896 | 0.875 | -4.942 | Likely Benign | 0.753 | Likely Pathogenic | Likely Benign | 0.059 | Likely Benign | -2.47 | Neutral | 0.033 | Benign | 0.017 | Benign | 3.90 | Benign | 0.01 | Affected | 0.2646 | 0.7584 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.2375A>C | E792A 2D AIThe SynGAP1 missense variant E792A is catalogued in gnomAD (ID 6‑33442927‑A‑C) but has no ClinVar submission. Functional prediction tools cluster into two groups: benign (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized) and pathogenic (PROVEAN, SIFT). The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.974374 | Disordered | 0.452261 | Uncertain | 0.352 | 0.896 | 0.875 | 6-33442927-A-C | 1 | 6.20e-7 | -3.248 | Likely Benign | 0.515 | Ambiguous | Likely Benign | 0.060 | Likely Benign | -3.35 | Deleterious | 0.000 | Benign | 0.001 | Benign | 3.92 | Benign | 0.01 | Affected | 3.64 | 6 | 0.4586 | 0.7544 | -1 | 0 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||||||
| c.2375A>G | E792G 2D AIThe SynGAP1 E792G 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 and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic vote). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as benign, and Foldetta results are unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.974374 | Disordered | 0.452261 | Uncertain | 0.352 | 0.896 | 0.875 | -3.925 | Likely Benign | 0.353 | Ambiguous | Likely Benign | 0.037 | Likely Benign | -3.77 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.88 | Benign | 0.01 | Affected | 0.3145 | 0.6036 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||||||||||||
| c.2378A>T | K793M 2D AIThe SynGAP1 K793M missense change is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, 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. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Overall, the balance of evidence, including the two high‑accuracy tools, points to a benign effect for K793M. 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 | SH3-binding motif | 0.971072 | Disordered | 0.426071 | Uncertain | 0.344 | 0.901 | 0.875 | -4.762 | Likely Benign | 0.570 | Likely Pathogenic | Likely Benign | 0.073 | Likely Benign | -1.49 | Neutral | 0.820 | Possibly Damaging | 0.601 | Possibly Damaging | 4.06 | Benign | 0.01 | Affected | 0.1674 | 0.4020 | 0 | -1 | 5.8 | 3.02 | ||||||||||||||||||||||||||||||||||||||
| c.2387C>A | P796Q 2D AIThe SynGAP1 missense variant P796Q 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 substitution as benign, while the only tool predicting a deleterious outcome is SIFT, which labels it pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) indicates likely benign; no Foldetta stability data are available. Overall, the consensus of the majority of predictors and the high‑accuracy tools points to a benign effect for P796Q, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar classification, as no pathogenic claim is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.936162 | Disordered | 0.426363 | Uncertain | 0.427 | 0.900 | 0.875 | -6.575 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.15 | Neutral | 0.325 | Benign | 0.103 | Benign | 4.27 | Benign | 0.01 | Affected | 0.1562 | 0.4117 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2387C>G | P796R 2D AIThe SynGAP1 P796R missense change 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), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Taken together, the overwhelming 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 | SH3-binding motif | 0.936162 | Disordered | 0.426363 | Uncertain | 0.427 | 0.900 | 0.875 | -7.053 | In-Between | 0.191 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.57 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.28 | Benign | 0.01 | Affected | 0.1558 | 0.2934 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2387C>T | P796L 2D AIThe SynGAP1 P796L missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). 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. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.936162 | Disordered | 0.426363 | Uncertain | 0.427 | 0.900 | 0.875 | -5.442 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.06 | Neutral | 0.325 | Benign | 0.182 | Benign | 4.24 | Benign | 0.01 | Affected | 0.2328 | 0.5712 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||||
| c.2404G>C | G802R 2D AIThe SynGAP1 missense variant G802R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only SIFT predicts a pathogenic effect, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus (majority vote) likewise predicts likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for G802R, 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 | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -4.756 | Likely Benign | 0.504 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.05 | Neutral | 0.259 | Benign | 0.196 | Benign | 2.68 | Benign | 0.01 | Affected | 0.0995 | 0.4514 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2410G>C | D804H 2D AIThe SynGAP1 D804H missense variant is not reported in ClinVar and is absent from gnomAD. 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 and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity, while the lack of a Foldetta result leaves that evidence inconclusive. Overall, the preponderance of pathogenic predictions suggests that D804H is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -5.100 | Likely Benign | 0.821 | Likely Pathogenic | Ambiguous | 0.296 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.975 | Probably Damaging | 1.19 | Pathogenic | 0.01 | Affected | 0.1859 | 0.7607 | 1 | -1 | 0.3 | 22.05 | ||||||||||||||||||||||||||||||||||||||
| c.2410G>T | D804Y 2D AIThe SynGAP1 missense variant D804Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic outcome. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, therefore classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus remains pathogenic; Foldetta results are unavailable. Overall, the majority of predictions support a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -8.356 | Likely Pathogenic | 0.782 | Likely Pathogenic | Likely Benign | 0.357 | Likely Benign | -5.16 | Deleterious | 0.999 | Probably Damaging | 0.983 | Probably Damaging | 1.18 | Pathogenic | 0.01 | Affected | 0.0886 | 0.6653 | -4 | -3 | 2.2 | 48.09 | ||||||||||||||||||||||||||||||||||||||
| 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.2420A>C | Y807S 2D AIThe SynGAP1 Y807S variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b, while those that predict pathogenicity are PROVEAN, SIFT, and FATHMM. AlphaMissense‑Default is uncertain, whereas AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of conventional tools (four benign vs. three pathogenic) suggest a benign effect, and the high‑accuracy AlphaMissense‑Optimized also predicts benign, while the SGM Consensus predicts pathogenic. Based on the balance of evidence, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | -5.517 | Likely Benign | 0.384 | Ambiguous | Likely Benign | 0.093 | Likely Benign | -3.90 | Deleterious | 0.136 | Benign | 0.067 | Benign | 2.44 | Pathogenic | 0.01 | Affected | 0.4561 | 0.1884 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||||
| c.2420A>G | Y807C 2D AIThe SynGAP1 missense variant Y807C is listed in ClinVar with an “Uncertain” status (ClinVar ID 2119812.0) and is present in gnomAD (ID 6‑33442972‑A‑G). Prediction tools that agree on a benign effect include REVEL, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts 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 (five pathogenic vs. three benign) and the SGM Consensus support a pathogenic interpretation, whereas AlphaMissense‑Optimized alone suggests benign. The variant is most likely pathogenic based on the collective evidence, and this conclusion is not contradicted by the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.699094 | Disordered | 0.853760 | Binding | 0.336 | 0.901 | 0.500 | Uncertain | 1 | 6-33442972-A-G | 1 | 6.20e-7 | -7.228 | In-Between | 0.204 | Likely Benign | Likely Benign | 0.243 | Likely Benign | -3.89 | Deleterious | 0.997 | Probably Damaging | 0.934 | Probably Damaging | 2.42 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3101 | 0.1907 | 0 | -2 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||
| c.2425A>C | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, 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. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2425A>T | S809C 2D AIThe SynGAP1 missense variant S809C is not 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 and HumVar), SIFT, ESM1b, and FATHMM. The SGM Consensus, which is a majority vote among 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. High‑accuracy tools specifically show AlphaMissense‑Optimized as benign, while SGM Consensus and Foldetta are unavailable. Overall, the majority of predictions (5 pathogenic vs. 4 benign) indicate that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -8.186 | Likely Pathogenic | 0.221 | Likely Benign | Likely Benign | 0.145 | Likely Benign | -1.99 | Neutral | 0.975 | Probably Damaging | 0.766 | Possibly Damaging | 2.49 | Pathogenic | 0.01 | Affected | 0.1088 | 0.6174 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.2426G>T | S809I 2D AIThe SynGAP1 missense variant S809I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from standard in silico predictors shows a split: six tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Optimized) predict a benign effect, while two (SIFT, AlphaMissense‑Default) predict pathogenicity; ESM1b is uncertain. High‑accuracy assessment further supports a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign classification, and Foldetta data are unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.708 | In-Between | 0.632 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -1.93 | Neutral | 0.065 | Benign | 0.022 | Benign | 2.50 | Benign | 0.01 | Affected | 0.1039 | 0.5984 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||||||||||||
| c.2427C>A | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, 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. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2427C>G | S809R 2D AIThe SynGAP1 missense variant S809R is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into three groups: benign predictions from REVEL, PROVEAN, and FATHMM; pathogenic predictions from polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; and uncertain predictions from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward benign. Protein‑folding stability analysis with Foldetta is unavailable. Overall, the balance of evidence, particularly the benign consensus from high‑accuracy tools, suggests the variant is most likely benign, 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. | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -7.062 | In-Between | 0.935 | Likely Pathogenic | Ambiguous | 0.091 | Likely Benign | -1.50 | Neutral | 0.784 | Possibly Damaging | 0.472 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.0954 | 0.3702 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.2428C>A | R810S 2D AIThe SynGAP1 R810S missense variant is not reported in ClinVar and is absent from gnomAD. 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 the SGM‑Consensus score. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. The high‑accuracy consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) favors pathogenicity, while the lack of a Foldetta result leaves that evidence inconclusive. Overall, the preponderance of pathogenic predictions suggests that R810S is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -5.996 | Likely Benign | 0.950 | Likely Pathogenic | Ambiguous | 0.204 | Likely Benign | -3.20 | Deleterious | 0.996 | Probably Damaging | 0.900 | Possibly Damaging | 2.44 | Pathogenic | 0.01 | Affected | 0.3152 | 0.4556 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.2428C>G | R810G 2D AISynGAP1 missense variant R810G is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: a single benign call from REVEL, and six pathogenic calls from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. Two tools (ESM1b and AlphaMissense‑Optimized) give uncertain results. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports the variant as Likely Pathogenic, and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic impact for R810G, 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 | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -7.190 | In-Between | 0.828 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | -3.57 | Deleterious | 0.996 | Probably Damaging | 0.925 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 0.3686 | 0.4207 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.2429G>A | R810H 2D AIThe SynGAP1 R810H missense variant is listed in gnomAD (ID 6‑33442981‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (FoldX‑MD/Rosetta stability analysis) is unavailable. Overall, the majority of tools predict pathogenicity, and the high‑accuracy subset is split, but the pathogenic signal dominates. Thus, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | 6-33442981-G-A | 3 | 1.86e-6 | -6.554 | Likely Benign | 0.550 | Ambiguous | Likely Benign | 0.239 | Likely Benign | -2.80 | Deleterious | 1.000 | Probably Damaging | 0.980 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.3149 | 0.2631 | 0 | 2 | 1.3 | -19.05 | ||||||||||||||||||||||||||||||||||
| c.2429G>C | R810P 2D AIThe SynGAP1 missense variant R810P is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, while pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further support a pathogenic bias: AlphaMissense‑Optimized indicates a benign effect, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant 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 from multiple in silico predictors points to a pathogenic impact for R810P. This conclusion is not contradicted by 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 | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -4.120 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.316 | Likely Benign | -4.08 | Deleterious | 1.000 | Probably Damaging | 0.977 | Probably Damaging | 2.33 | Pathogenic | 0.01 | Affected | 0.2307 | 0.5478 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||
| c.2429G>T | R810L 2D AIThe SynGAP1 R810L missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, while the majority of algorithms (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Uncertain calls come from ESM1b and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic, and Foldetta results are unavailable. Overall, the preponderance of evidence from multiple in‑silico predictors points to a pathogenic impact for R810L. 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 | SH3-binding motif | 0.486429 | Structured | 0.851848 | Binding | 0.263 | 0.907 | 0.375 | -7.172 | In-Between | 0.834 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | -4.57 | Deleterious | 0.996 | Probably Damaging | 0.925 | Probably Damaging | 2.35 | Pathogenic | 0.01 | Affected | 0.2019 | 0.5271 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||
| c.2432C>A | P811Q 2D AIThe SynGAP1 missense variant P811Q 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 polyPhen‑2 (HumDiv and HumVar) and SIFT 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 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 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. | Likely Benign | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.145 | Likely Benign | 0.431 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -2.38 | Neutral | 0.982 | Probably Damaging | 0.875 | Possibly Damaging | 2.78 | Benign | 0.01 | Affected | 0.1523 | 0.5338 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||||
| c.2432C>G | P811R 2D AIThe SynGAP1 missense variant P811R is not 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 and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT; AlphaMissense‑Default remains uncertain. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, with one uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the preponderance of evidence points to a benign impact for P811R, 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. | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -5.273 | Likely Benign | 0.557 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -2.69 | Deleterious | 0.100 | Benign | 0.066 | Benign | 2.73 | Benign | 0.01 | Affected | 0.1448 | 0.3817 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2432C>T | P811L 2D AIThe SynGAP1 P811L missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. AlphaMissense‑Default is uncertain. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, leans toward benign (2 benign vs. 1 pathogenic, 1 uncertain). AlphaMissense‑Optimized also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from high‑accuracy tools and consensus methods indicates that P811L is most likely benign. This assessment does not contradict ClinVar status, as the variant is not yet reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.411940 | Structured | 0.847064 | Binding | 0.382 | 0.910 | 0.250 | -6.184 | Likely Benign | 0.491 | Ambiguous | Likely Benign | 0.150 | Likely Benign | -3.98 | Deleterious | 0.982 | Probably Damaging | 0.824 | Possibly Damaging | 2.71 | Benign | 0.01 | Affected | 0.2327 | 0.6621 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.2435C>G | P812R 2D AIThe SynGAP1 P812R 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 agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of standard predictors indicate a pathogenic impact, while the most accurate tools provide no definitive evidence. Thus, the variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | -6.784 | Likely Benign | 0.799 | Likely Pathogenic | Ambiguous | 0.222 | Likely Benign | -2.70 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.77 | Benign | 0.01 | Affected | 0.1285 | 0.3525 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.2435C>T | P812L 2D AIThe SynGAP1 P812L missense variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33442987‑C‑T). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta’s protein‑folding stability analysis is unavailable. Overall, the majority of predictions lean toward pathogenicity, which is consistent with the lack of ClinVar reporting but does not contradict it. 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. | SH3-binding motif | 0.414856 | Structured | 0.842442 | Binding | 0.388 | 0.901 | 0.125 | 6-33442987-C-T | 1 | 6.20e-7 | -7.121 | In-Between | 0.591 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -2.61 | Deleterious | 0.978 | Probably Damaging | 0.824 | Possibly Damaging | 2.76 | Benign | 0.01 | Affected | 4.32 | 4 | 0.2131 | 0.6634 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.2441C>A | A814D 2D AIThe SynGAP1 missense variant A814D is not 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 a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a tie and thus unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no reported result. Overall, the balance of evidence from the consensus of standard predictors points to a pathogenic 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. | SH3-binding motif | 0.411940 | Structured | 0.814830 | Binding | 0.368 | 0.902 | 0.250 | -5.641 | Likely Benign | 0.939 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -2.56 | Deleterious | 0.968 | Probably Damaging | 0.810 | Possibly Damaging | 2.59 | Benign | 0.01 | Affected | 0.1740 | 0.2167 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||||||||||||
| c.2455G>A | A819T 2D AIThe SynGAP1 missense variant A819T is not 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 AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign) and Foldetta data are unavailable. Overall, the majority of conventional predictors lean toward pathogenicity, but the single high‑accuracy tool predicts benign and the consensus is unresolved. Thus, the variant is most likely pathogenic 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. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -3.421 | Likely Benign | 0.675 | Likely Pathogenic | Likely Benign | 0.287 | Likely Benign | -2.23 | Neutral | 0.998 | Probably Damaging | 0.963 | Probably Damaging | 2.29 | Pathogenic | 0.01 | Affected | 0.1443 | 0.7583 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2455G>C | A819P 2D AIThe SynGAP1 missense variant A819P 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, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and 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—classifies the variant as likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence points to a pathogenic impact for A819P, 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 | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | -5.542 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.342 | Likely Benign | -3.18 | Deleterious | 0.999 | Probably Damaging | 0.985 | Probably Damaging | 2.17 | Pathogenic | 0.01 | Affected | 0.1920 | 0.5753 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.2456C>T | A819V 2D AIThe SynGAP1 missense variant A819V is catalogued in gnomAD (ID 6‑33443008‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, and ESM1b, whereas a majority of tools predict a pathogenic outcome: polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two benign vs. two pathogenic), and Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a pathogenic classification for A819V, and this assessment does not contradict any ClinVar status because the variant is not yet reported in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.694846 | Disordered | 0.707644 | Binding | 0.317 | 0.892 | 0.625 | 6-33443008-C-T | 1 | 6.19e-7 | -4.944 | Likely Benign | 0.797 | Likely Pathogenic | Ambiguous | 0.246 | Likely Benign | -2.40 | Neutral | 0.998 | Probably Damaging | 0.963 | Probably Damaging | 2.19 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1098 | 0.6664 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||
| c.2462G>A | C821Y 2D AIThe SynGAP1 missense variant C821Y is not 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 impact: 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 vs 2), and Foldetta results are unavailable. Overall, seven tools support pathogenicity while three support benignity, and no high‑accuracy consensus contradicts this trend. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -1.007 | Likely Benign | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.342 | Likely Benign | -3.11 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.66 | Benign | 0.01 | Affected | 0.1288 | 0.3187 | 0 | -2 | -3.8 | 60.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2462G>T | C821F 2D AIThe SynGAP1 missense variant C821F is not 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 a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict any existing 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. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | 0.971 | Likely Benign | 0.924 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | -3.33 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.66 | Benign | 0.01 | Affected | 0.1504 | 0.3505 | -4 | -2 | 0.3 | 44.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2463C>G | C821W 2D AIThe SynGAP1 missense variant C821W is not 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. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates 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 evaluated predictors (six pathogenic vs three benign) indicate a pathogenic impact. This prediction 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. | 0.745909 | Disordered | 0.672821 | Binding | 0.351 | 0.883 | 0.750 | -4.843 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.201 | Likely Benign | -3.30 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.64 | Benign | 0.01 | Affected | 0.1742 | 0.3268 | -8 | -2 | -3.4 | 83.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2474C>T | S825L 2D AIThe SynGAP1 missense variant S825L is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443026‑C‑T). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, 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 Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” and the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, 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 | 0.675549 | Disordered | 0.618614 | Binding | 0.384 | 0.886 | 0.750 | Uncertain | 1 | 6-33443026-C-T | 1 | 6.20e-7 | -4.987 | Likely Benign | 0.910 | Likely Pathogenic | Ambiguous | 0.249 | Likely Benign | -4.30 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1252 | 0.5747 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||
| c.2476G>A | D826N 2D AIThe SynGAP1 missense variant D826N has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on benign effects include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict pathogenicity are 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 show AlphaMissense‑Optimized as Uncertain, and Foldetta results are unavailable. Given the balance of evidence, the majority of high‑confidence predictions and the SGM consensus favor a benign outcome. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -3.663 | Likely Benign | 0.907 | Likely Pathogenic | Ambiguous | 0.154 | Likely Benign | -2.24 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.54 | Benign | 0.01 | Affected | 0.1520 | 0.8248 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
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