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.3528A>C | E1176D 2D  AIThe SynGAP1 E1176D missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified 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. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.538167 | Disordered | 0.572075 | Binding | 0.525 | 0.715 | 0.250 | -4.603 | Likely Benign | 0.731 | Likely Pathogenic | Likely Benign | 0.322 | Likely Benign | -0.81 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 5.44 | Benign | 0.31 | Tolerated | 0.1419 | 0.4026 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3528A>T | E1176D 2D AIThe SynGAP1 missense variant E1176D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.538167 | Disordered | 0.572075 | Binding | 0.525 | 0.715 | 0.250 | -4.603 | Likely Benign | 0.731 | Likely Pathogenic | Likely Benign | 0.322 | Likely Benign | -0.81 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 5.44 | Benign | 0.31 | Tolerated | 0.1419 | 0.4026 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3529G>A | E1177K 2D  AISynGAP1 missense variant E1177K is listed in ClinVar with an Uncertain significance status and is not reported in gnomAD. Functional prediction tools show a split: benign calls come from PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments give AlphaMissense‑Optimized as Uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign effect, which does not contradict the ClinVar designation of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.566503 | Binding | 0.542 | 0.705 | 0.250 | Uncertain | 1 | -3.413 | Likely Benign | 0.944 | Likely Pathogenic | Ambiguous | 0.560 | Likely Pathogenic | -1.75 | Neutral | 0.905 | Possibly Damaging | 0.637 | Possibly Damaging | 5.44 | Benign | 0.11 | Tolerated | 4.32 | 2 | 0.1471 | 0.4424 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||
| c.3532T>A | Y1178N 2D  AIThe SynGAP1 missense variant Y1178N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools are divided: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -2.125 | Likely Benign | 0.619 | Likely Pathogenic | Likely Benign | 0.410 | Likely Benign | -1.18 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 5.50 | Benign | 0.09 | Tolerated | 0.2456 | 0.0341 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.3532T>G | Y1178D 2D  AIThe SynGAP1 missense variant Y1178D is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Optimized yields an Uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available prediction for this variant. Overall, the balance of evidence from high‑accuracy tools and consensus predictions leans toward a benign classification. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -1.250 | Likely Benign | 0.801 | Likely Pathogenic | Ambiguous | 0.434 | Likely Benign | -1.33 | Neutral | 0.995 | Probably Damaging | 0.846 | Possibly Damaging | 5.55 | Benign | 0.07 | Tolerated | 0.4562 | 0.0173 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.3533A>C | Y1178S 2D  AIThe SynGAP1 missense variant Y1178S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence from both general and high‑accuracy tools 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 | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -1.440 | Likely Benign | 0.771 | Likely Pathogenic | Likely Benign | 0.329 | Likely Benign | -1.53 | Neutral | 0.983 | Probably Damaging | 0.769 | Possibly Damaging | 5.57 | Benign | 0.33 | Tolerated | 0.5225 | 0.1626 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||
| c.3533A>T | Y1178F 2D  AIThe SynGAP1 missense variant Y1178F is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Foldetta results are unavailable. Based on the consensus of all available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.568433 | Binding | 0.554 | 0.688 | 0.250 | -3.081 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.162 | Likely Benign | -0.64 | Neutral | 0.012 | Benign | 0.017 | Benign | 5.44 | Benign | 0.24 | Tolerated | 0.1893 | 0.2758 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.353T>C | M118T 2D  AIThe SynGAP1 missense variant M118T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM‑Consensus) also indicates a likely benign classification, and AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the evidence from multiple independent predictors and the high‑accuracy consensus strongly supports a benign impact. This conclusion is consistent with the lack of any ClinVar pathogenic 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 Benign | 0.694846 | Disordered | 0.676867 | Binding | 0.330 | 0.883 | 0.500 | -2.468 | Likely Benign | 0.454 | Ambiguous | Likely Benign | 0.217 | Likely Benign | -2.41 | Neutral | 0.396 | Benign | 0.067 | Benign | 3.86 | Benign | 0.08 | Tolerated | 0.2207 | 0.2237 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||||||||||||||
| c.3541A>C | K1181Q 2D  AIThe SynGAP1 K1181Q missense variant is reported in gnomAD (variant ID 6‑33444576‑A‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.539278 | Binding | 0.625 | 0.660 | 0.375 | 6-33444576-A-C | -3.724 | Likely Benign | 0.779 | Likely Pathogenic | Likely Benign | 0.173 | Likely Benign | -1.48 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 2.66 | Benign | 0.07 | Tolerated | 4.32 | 3 | 0.3415 | 0.1102 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||
| c.3541A>G | K1181E 2D  AIThe SynGAP1 missense variant K1181E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense (Default and Optimized) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.539278 | Binding | 0.625 | 0.660 | 0.375 | -3.244 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.196 | Likely Benign | -1.19 | Neutral | 0.995 | Probably Damaging | 0.949 | Probably Damaging | 2.86 | Benign | 0.55 | Tolerated | 0.2862 | 0.0877 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3542A>G | K1181R 2D  AIThe SynGAP1 missense variant K1181R is reported in gnomAD (variant ID 6‑33444577‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, representing the sole discordant prediction. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.539278 | Binding | 0.625 | 0.660 | 0.375 | 6-33444577-A-G | 2 | 1.24e-6 | -2.786 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.90 | Neutral | 0.573 | Possibly Damaging | 0.429 | Benign | 2.67 | Benign | 0.07 | Tolerated | 4.32 | 3 | 0.3533 | 0.0878 | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||
| c.3546G>C | E1182D 2D AIThe SynGAP1 missense variant E1182D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support this: AlphaMissense‑Optimized indicates benign, while the SGM‑Consensus (majority vote) 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 evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.400 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 0.106 | Likely Benign | -0.87 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.62 | Benign | 0.34 | Tolerated | 0.1480 | 0.4161 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3546G>T | E1182D 2D AIThe SynGAP1 missense change E1182D is not reported in ClinVar and has no allele in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the absence of ClinVar annotation or gnomAD observation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.530232 | Binding | 0.597 | 0.651 | 0.375 | -4.400 | Likely Benign | 0.760 | Likely Pathogenic | Likely Benign | 0.106 | Likely Benign | -0.87 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.62 | Benign | 0.34 | Tolerated | 0.1480 | 0.4161 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3547T>A | Y1183N 2D AIThe SynGAP1 missense variant Y1183N 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, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score (Likely Benign). In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default all predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome; Foldetta predictions are unavailable. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -3.413 | Likely Benign | 0.890 | Likely Pathogenic | Ambiguous | 0.083 | Likely Benign | -1.44 | Neutral | 0.905 | Possibly Damaging | 0.543 | Possibly Damaging | 2.88 | Benign | 0.35 | Tolerated | 0.2368 | 0.0243 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.3547T>C | Y1183H 2D  AIThe SynGAP1 missense variant Y1183H 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), SIFT, ESM1b, and FATHMM, all of which classify the substitution as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. In contrast, AlphaMissense‑Default predicts a pathogenic effect, while AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and no Foldetta stability data are available. Overall, the preponderance of evidence points to a benign impact for Y1183H, 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 | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -3.289 | Likely Benign | 0.925 | Likely Pathogenic | Ambiguous | 0.026 | Likely Benign | -0.70 | Neutral | 0.029 | Benign | 0.017 | Benign | 2.75 | Benign | 0.18 | Tolerated | 0.2227 | 0.0243 | 0 | 2 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||||||
| c.3547T>G | Y1183D 2D AISynGAP1 missense variant Y1183D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, a majority‑vote model of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts the variant as likely benign. High‑accuracy assessments further indicate AlphaMissense‑Optimized as pathogenic, whereas Foldetta (FoldX‑MD/Rosetta stability analysis) is not available for this residue. Overall, the balance of evidence leans toward a benign effect, and this assessment does not conflict with ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -2.718 | Likely Benign | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | -1.10 | Neutral | 0.986 | Probably Damaging | 0.787 | Possibly Damaging | 2.83 | Benign | 0.61 | Tolerated | 0.4602 | 0.0243 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.3548A>C | Y1183S 2D AIThe SynGAP1 missense variant Y1183S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, PROVEAN, SIFT, ESM1b, FATHMM) and pathogenic predictions (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign impact for Y1183S, 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 | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -2.514 | Likely Benign | 0.961 | Likely Pathogenic | Likely Pathogenic | 0.164 | Likely Benign | -1.57 | Neutral | 0.951 | Possibly Damaging | 0.619 | Possibly Damaging | 2.86 | Benign | 0.51 | Tolerated | 0.5346 | 0.1096 | Weaken | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||||||||||
| c.3548A>G | Y1183C 2D  AIThe SynGAP1 missense variant Y1183C is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -5.585 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.261 | Likely Benign | -2.69 | Deleterious | 0.999 | Probably Damaging | 0.917 | Probably Damaging | 2.76 | Benign | 0.06 | Tolerated | 0.3449 | 0.1955 | 0 | -2 | 3.8 | -60.04 | |||||||||||||||||||||||||||||||||||||||
| c.3548A>T | Y1183F 2D AIThe SynGAP1 missense variant Y1183F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods give a benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no Foldetta data. 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 | Coiled-coil | 0.566480 | Disordered | 0.527818 | Binding | 0.523 | 0.652 | 0.500 | -3.527 | Likely Benign | 0.446 | Ambiguous | Likely Benign | 0.124 | Likely Benign | -1.42 | Neutral | 0.951 | Possibly Damaging | 0.514 | Possibly Damaging | 2.74 | Benign | 0.23 | Tolerated | 0.1891 | 0.2829 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3550T>A | S1184T 2D  AIThe SynGAP1 missense variant S1184T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence from multiple prediction algorithms and consensus 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 | Coiled-coil | 0.648219 | Disordered | 0.514669 | Binding | 0.624 | 0.642 | 0.500 | -4.250 | Likely Benign | 0.712 | Likely Pathogenic | Likely Benign | 0.085 | Likely Benign | -1.27 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.70 | Benign | 0.18 | Tolerated | 0.1212 | 0.5004 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3550T>C | S1184P 2D  AIThe SynGAP1 missense variant S1184P is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the majority of tools and the consensus prediction lean toward a benign interpretation, 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 Benign | Coiled-coil | 0.648219 | Disordered | 0.514669 | Binding | 0.624 | 0.642 | 0.500 | -4.829 | Likely Benign | 0.995 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -1.38 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.66 | Benign | 0.16 | Tolerated | 0.1772 | 0.4569 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||
| c.3550T>G | S1184A 2D  AIThe SynGAP1 missense variant S1184A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools are divided: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.648219 | Disordered | 0.514669 | Binding | 0.624 | 0.642 | 0.500 | -3.753 | Likely Benign | 0.595 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -1.11 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.73 | Benign | 0.51 | Tolerated | 0.4093 | 0.3850 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3551C>T | S1184L 2D  AIThe SynGAP1 missense variant S1184L has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the balance of evidence from high‑accuracy tools leans toward a benign classification, and this assessment does not contradict any ClinVar status, as none exists for S1184L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.648219 | Disordered | 0.514669 | Binding | 0.624 | 0.642 | 0.500 | -2.595 | Likely Benign | 0.939 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.87 | Neutral | 0.991 | Probably Damaging | 0.987 | Probably Damaging | 2.75 | Benign | 0.06 | Tolerated | 0.0822 | 0.4577 | -3 | -2 | 4.6 | 26.08 | ||||||||||||||||||||||||||||||||||||||
| c.3553A>C | K1185Q 2D AIThe SynGAP1 K1185Q missense change is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. AlphaMissense‑Optimized yields an uncertain result, and no Foldetta stability assessment is available. Considering the high‑accuracy evidence, the consensus remains “Likely Benign” and the AlphaMissense‑Optimized prediction is inconclusive. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | -4.256 | Likely Benign | 0.865 | Likely Pathogenic | Ambiguous | 0.125 | Likely Benign | -0.92 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.74 | Benign | 0.37 | Tolerated | 0.4371 | 0.0945 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3553A>G | K1185E 2D AISynGAP1 K1185E is not reported in ClinVar and has no gnomAD allele. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further highlight this divergence: AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus (a majority‑vote method) indicates benign; Foldetta results are unavailable. Overall, the balance of evidence, including the consensus from multiple predictors, points to a benign effect. Thus, the variant is most likely benign, 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 Benign | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | -4.465 | Likely Benign | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.148 | Likely Benign | -1.34 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.89 | Benign | 0.19 | Tolerated | 0.3715 | 0.0720 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3554A>C | K1185T 2D  AIThe SynGAP1 missense variant K1185T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | -4.771 | Likely Benign | 0.970 | Likely Pathogenic | Likely Pathogenic | 0.153 | Likely Benign | -2.41 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.67 | Benign | 0.13 | Tolerated | 0.2256 | 0.2700 | 0 | -1 | 3.2 | -27.07 | ||||||||||||||||||||||||||||||||||||||
| c.3554A>G | K1185R 2D AIThe SynGAP1 missense variant K1185R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: 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 K1185R, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | -2.898 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -0.48 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 2.67 | Benign | 0.66 | Tolerated | 0.4476 | 0.0909 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.3554A>T | K1185I 2D  AIThe SynGAP1 missense variant K1185I is listed in ClinVar with no pathogenicity classification (ClinVar status: None) and is present in the gnomAD database (gnomAD ID: 6‑33444589‑A‑T). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta results are unavailable. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | 6-33444589-A-T | 1 | 6.20e-7 | -5.101 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.215 | Likely Benign | -3.42 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.62 | Benign | 0.09 | Tolerated | 3.82 | 4 | 0.1154 | 0.3108 | -3 | -2 | 8.4 | -15.01 | ||||||||||||||||||||||||||||||||||
| c.3555A>C | K1185N 2D  AIThe SynGAP1 missense variant K1185N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default both predict a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as likely benign, whereas AlphaMissense‑Optimized predicts pathogenicity. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions lean toward a benign interpretation, and there is no ClinVar entry to contradict this assessment. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | -4.345 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.093 | Likely Benign | -2.04 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.68 | Benign | 0.12 | Tolerated | 0.3653 | 0.1145 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3555A>T | K1185N 2D AIThe SynGAP1 missense variant K1185N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a mixed signal: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments further split the verdict: AlphaMissense‑Optimized predicts Pathogenic, whereas the SGM‑Consensus (majority vote) indicates Likely Benign; Foldetta results are unavailable. Overall, the balance of evidence slightly favors a benign interpretation, and there is no conflict with ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.566480 | Disordered | 0.510264 | Binding | 0.642 | 0.638 | 0.625 | -4.345 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.093 | Likely Benign | -2.04 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.68 | Benign | 0.12 | Tolerated | 0.3653 | 0.1145 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||||||||||
| c.3556T>A | S1186T 2D AIThe SynGAP1 missense variant S1186T is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign, whereas polyPhen‑2 (HumDiv and HumVar) predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the four high‑accuracy tools) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that S1186T 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 | Coiled-coil | 0.562014 | Disordered | 0.506433 | Binding | 0.634 | 0.636 | 0.625 | -5.145 | Likely Benign | 0.528 | Ambiguous | Likely Benign | 0.111 | Likely Benign | -1.47 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.67 | Benign | 0.13 | Tolerated | 0.1128 | 0.4442 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3556T>C | S1186P 2D AIThe SynGAP1 missense variant S1186P lies in a coiled‑coil domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta results are unavailable. Overall, the balance of evidence leans toward pathogenicity, with no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.506433 | Binding | 0.634 | 0.636 | 0.625 | -6.365 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.198 | Likely Benign | -2.51 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.09 | Tolerated | 0.1784 | 0.4006 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3556T>G | S1186A 2D AIThe SynGAP1 missense variant S1186A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are AlphaMissense‑Default, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.506433 | Binding | 0.634 | 0.636 | 0.625 | -5.226 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -1.45 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.69 | Benign | 0.16 | Tolerated | 0.4636 | 0.3487 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3559A>C | M1187L 2D  AIThe SynGAP1 missense variant M1187L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is not available for this variant. Based on the majority of predictions and the high‑accuracy consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -2.192 | Likely Benign | 0.772 | Likely Pathogenic | Likely Benign | 0.483 | Likely Benign | -1.27 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 5.48 | Benign | 1.00 | Tolerated | 0.1680 | 0.3637 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3559A>G | M1187V 2D  AIThe M1187V missense change in SynGAP1’s coiled‑coil domain is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -3.107 | Likely Benign | 0.733 | Likely Pathogenic | Likely Benign | 0.478 | Likely Benign | -1.44 | Neutral | 0.843 | Possibly Damaging | 0.926 | Probably Damaging | 5.49 | Benign | 0.19 | Tolerated | 0.3300 | 0.2800 | 2 | 1 | 2.3 | -32.06 | ||||||||||||||||||||||||||||||||||||||
| c.3559A>T | M1187L 2D AIThe SynGAP1 missense variant M1187L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign effect for M1187L, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -2.192 | Likely Benign | 0.772 | Likely Pathogenic | Likely Benign | 0.483 | Likely Benign | -1.27 | Neutral | 0.699 | Possibly Damaging | 0.833 | Possibly Damaging | 5.48 | Benign | 1.00 | Tolerated | 0.1680 | 0.3637 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3561G>A | M1187I 2D  AIThe SynGAP1 missense variant M1187I is reported in gnomAD (6‑33444596‑G‑A) and has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus (high‑accuracy) is benign; Foldetta results are unavailable. Overall, the balance of evidence—including the benign SGM‑Consensus and the majority of individual tools—suggests the variant is most likely benign, 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 Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | 6-33444596-G-A | 1 | 6.20e-7 | -3.666 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.366 | Likely Benign | -1.65 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 5.46 | Benign | 0.32 | Tolerated | 3.82 | 4 | 0.1480 | 0.3119 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||
| c.3561G>C | M1187I 2D AIThe SynGAP1 missense variant M1187I is not reported in ClinVar and has no gnomAD allele. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. A consensus analysis (SGM‑Consensus) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN votes yields a Likely Benign result. High‑accuracy assessments further indicate AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus remains benign; Foldetta data are unavailable. Overall, the majority of evidence (five benign versus four pathogenic predictions, plus a benign consensus) points to a benign effect. 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 Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -3.666 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.366 | Likely Benign | -1.65 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 5.46 | Benign | 0.32 | Tolerated | 3.82 | 4 | 0.1480 | 0.3119 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.3561G>T | M1187I 2D AIThe SynGAP1 missense variant M1187I is not reported in ClinVar and has no gnomAD allele. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. A consensus analysis (SGM‑Consensus) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN votes yields a Likely Benign result. High‑accuracy assessments further indicate AlphaMissense‑Optimized predicts pathogenic, whereas the SGM‑Consensus remains benign; Foldetta data are unavailable. Overall, the majority of evidence (five benign versus four pathogenic predictions, plus a benign consensus) points to a benign effect. 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 Benign | Coiled-coil | 0.562014 | Disordered | 0.499801 | Uncertain | 0.597 | 0.636 | 0.625 | -3.666 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.366 | Likely Benign | -1.65 | Neutral | 0.925 | Possibly Damaging | 0.954 | Probably Damaging | 5.46 | Benign | 0.32 | Tolerated | 3.82 | 4 | 0.1480 | 0.3119 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.3565G>A | E1189K 2D AIThe SynGAP1 missense variant E1189K is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta results are unavailable. Overall, the balance of evidence—five benign predictions versus three pathogenic ones, a consensus benign rating, and no conflicting ClinVar annotation—suggests that E1189K is most likely benign. This conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -5.565 | Likely Benign | 0.947 | Likely Pathogenic | Ambiguous | 0.423 | Likely Benign | -1.64 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.37 | Benign | 0.08 | Tolerated | 0.1597 | 0.4046 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3565G>C | E1189Q 2D  AIThe SynGAP1 missense variant E1189Q has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status (which is absent). Thus, the variant is most likely benign based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -4.977 | Likely Benign | 0.842 | Likely Pathogenic | Ambiguous | 0.338 | Likely Benign | -1.45 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.30 | Benign | 0.10 | Tolerated | 0.0738 | 0.3797 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3566A>C | E1189A 2D  AIThe SynGAP1 missense variant E1189A is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑vs‑2 split. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the predictions are evenly divided between benign and pathogenic, with no high‑confidence consensus. Thus, the variant is most likely of uncertain significance; there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -4.989 | Likely Benign | 0.860 | Likely Pathogenic | Ambiguous | 0.427 | Likely Benign | -3.06 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.34 | Benign | 0.09 | Tolerated | 0.2827 | 0.4105 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3567G>C | E1189D 2D AIThe SynGAP1 missense variant E1189D (gnomAD ID 6-33444602‑G‑C) is listed in ClinVar as Benign (ClinVar ID 833989.0). In silico predictors that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Predictors that indicate a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as benign, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also favors a benign outcome. No Foldetta stability assessment is available for this residue. Overall, the majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar designation, showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | Likely Benign | 1 | 6-33444602-G-C | 3 | 1.86e-6 | -3.582 | Likely Benign | 0.461 | Ambiguous | Likely Benign | 0.359 | Likely Benign | -1.42 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 5.30 | Benign | 0.25 | Tolerated | 3.82 | 4 | 0.1393 | 0.2610 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||
| c.3567G>T | E1189D 2D AIThe SynGAP1 missense variant E1189D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods reinforce the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, while Foldetta data are missing. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.562014 | Disordered | 0.466885 | Uncertain | 0.704 | 0.623 | 0.625 | -3.582 | Likely Benign | 0.461 | Ambiguous | Likely Benign | 0.359 | Likely Benign | -1.42 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 5.30 | Benign | 0.25 | Tolerated | 3.82 | 4 | 0.1393 | 0.2610 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3568A>G | S1190G 2D  AIThe SynGAP1 missense change S1190G is catalogued in gnomAD (ID 6‑33444603‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign (REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) and pathogenic (AlphaMissense‑Default, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar). 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. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Taken together, the preponderance of evidence 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 | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | 6-33444603-A-G | 1 | 6.20e-7 | -3.078 | Likely Benign | 0.647 | Likely Pathogenic | Likely Benign | 0.374 | Likely Benign | -1.13 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 5.28 | Benign | 0.42 | Tolerated | 3.82 | 4 | 0.2312 | 0.3549 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||
| c.3568A>T | S1190C 2D  AIThe SynGAP1 missense variant S1190C is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | -6.788 | Likely Benign | 0.828 | Likely Pathogenic | Ambiguous | 0.418 | Likely Benign | -1.93 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 5.22 | Benign | 0.07 | Tolerated | 0.1144 | 0.4294 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||
| c.3569G>A | S1190N 2D  AIThe SynGAP1 missense variant S1190N is catalogued in gnomAD (6‑33444604‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta results are unavailable. Overall, the balance of evidence favors a benign effect for S1190N, 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 | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | 6-33444604-G-A | 2 | 1.24e-6 | -4.909 | Likely Benign | 0.811 | Likely Pathogenic | Ambiguous | 0.326 | Likely Benign | -1.25 | Neutral | 0.991 | Probably Damaging | 0.988 | Probably Damaging | 5.27 | Benign | 0.07 | Tolerated | 3.82 | 4 | 0.1368 | 0.3441 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||
| c.3569G>C | S1190T 2D AIThe SynGAP1 missense variant S1190T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) predict a pathogenic outcome. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates 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 any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.455760 | Uncertain | 0.742 | 0.624 | 0.625 | -4.362 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.320 | Likely Benign | -1.02 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 5.35 | Benign | 0.19 | Tolerated | 0.1452 | 0.4352 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3572G>A | R1191Q 2D  AIThe SynGAP1 missense variant R1191Q is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33444607‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain”; the SGM‑Consensus (majority vote) remains “Likely Benign”; and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this is not contradictory to the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.439584 | Uncertain | 0.765 | 0.622 | 0.625 | Uncertain | 2 | 6-33444607-G-A | 9 | 5.58e-6 | -1.069 | Likely Benign | 0.943 | Likely Pathogenic | Ambiguous | 0.343 | Likely Benign | -1.41 | Neutral | 0.998 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.08 | Tolerated | 3.82 | 4 | 0.3107 | 0.2000 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||
| c.3574C>A | L1192M 2D  AIThe SynGAP1 missense variant L1192M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports a benign likelihood. 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, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.441757 | Uncertain | 0.762 | 0.609 | 0.625 | -4.591 | Likely Benign | 0.195 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -0.44 | Neutral | 0.606 | Possibly Damaging | 0.287 | Benign | 2.66 | Benign | 0.16 | Tolerated | 0.0669 | 0.2486 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3574C>G | L1192V 2D  AIThe SynGAP1 missense variant L1192V is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; 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. Thus, based on current predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.441757 | Uncertain | 0.762 | 0.609 | 0.625 | Uncertain | 1 | -4.132 | Likely Benign | 0.471 | Ambiguous | Likely Benign | 0.041 | Likely Benign | -0.89 | Neutral | 0.779 | Possibly Damaging | 0.527 | Possibly Damaging | 2.69 | Benign | 0.16 | Tolerated | 0.1441 | 0.2289 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3575T>A | L1192Q 2D  AIThe SynGAP1 missense variant L1192Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (both HumDiv and HumVar) 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 further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods points to a benign impact for this 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 Benign | Coiled-coil | 0.575842 | Disordered | 0.441757 | Uncertain | 0.762 | 0.609 | 0.625 | -3.804 | Likely Benign | 0.535 | Ambiguous | Likely Benign | 0.224 | Likely Benign | -1.09 | Neutral | 0.992 | Probably Damaging | 0.940 | Probably Damaging | 2.70 | Benign | 0.10 | Tolerated | 0.1032 | 0.0558 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3575T>G | L1192R 2D  AIThe SynGAP1 missense variant L1192R is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, 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, has no available result for this variant. Overall, the preponderance of evidence points to the variant being most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.575842 | Disordered | 0.441757 | Uncertain | 0.762 | 0.609 | 0.625 | -3.221 | Likely Benign | 0.695 | Likely Pathogenic | Likely Benign | 0.184 | Likely Benign | -1.33 | Neutral | 0.992 | Probably Damaging | 0.940 | Probably Damaging | 2.75 | Benign | 0.35 | Tolerated | 0.1148 | 0.0558 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.357G>C | E119D 2D AIThe SynGAP1 missense variant E119D is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | -3.258 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.08 | Benign | 0.32 | Tolerated | 3.61 | 5 | 0.2180 | 0.5759 | 2 | 3 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||||
| c.357G>T | E119D 2D AIThe SynGAP1 missense variant E119D is reported in gnomAD (variant ID 6‑33432222‑G‑T) but has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the evidence strongly supports a benign classification, 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 | 0.690604 | Disordered | 0.661946 | Binding | 0.346 | 0.881 | 0.750 | 6-33432222-G-T | 3 | 1.86e-6 | -3.258 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.033 | Likely Benign | 0.07 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.08 | Benign | 0.32 | Tolerated | 3.61 | 5 | 0.2180 | 0.5759 | 2 | 3 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||||
| c.3581G>A | R1194K 2D  AIThe SynGAP1 missense variant R1194K is catalogued in gnomAD (6‑33444616‑G‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Pathogenic predictions are reported by both polyPhen‑2 HumDiv and HumVar. AlphaMissense‑Default is uncertain, and no Foldetta stability assessment is available. High‑accuracy evidence is consistent with benign impact: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also indicates a likely benign outcome. In the absence of any pathogenic signal from these robust predictors and with no ClinVar classification to contradict, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.685117 | Disordered | 0.425297 | Uncertain | 0.796 | 0.602 | 0.375 | 6-33444616-G-A | 1 | 6.21e-7 | -2.501 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.380 | Likely Benign | -0.97 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 5.56 | Benign | 0.14 | Tolerated | 3.77 | 5 | 0.4637 | 0.3297 | 2 | 3 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||
| c.3583G>C | V1195L 2D  AIThe SynGAP1 missense variant V1195L has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Considering the high‑accuracy tools, the consensus leans toward benign (SGM‑Consensus) with no definitive pathogenic signal from AlphaMissense‑Optimized or Foldetta. Overall, the majority of evidence supports a benign impact, and this assessment does not contradict any ClinVar status, as none exists for V1195L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -2.603 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.323 | Likely Benign | -0.84 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.46 | Benign | 0.70 | Tolerated | 0.0695 | 0.3827 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3583G>T | V1195L 2D AIThe SynGAP1 missense variant V1195L has no ClinVar record and is not listed in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. AlphaMissense‑Optimized is uncertain, and no Foldetta stability assessment is available. Overall, the majority of high‑confidence predictors (six benign vs. three pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign, 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 | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -2.603 | Likely Benign | 0.928 | Likely Pathogenic | Ambiguous | 0.305 | Likely Benign | -0.84 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.46 | Benign | 0.70 | Tolerated | 0.0695 | 0.3827 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3584T>C | V1195A 2D  AIThe SynGAP1 missense variant V1195A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default both predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, whereas the SGM‑Consensus remains likely benign; Foldetta results are not available. Overall, the balance of evidence leans toward a benign impact, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.604312 | Disordered | 0.434133 | Uncertain | 0.842 | 0.603 | 0.250 | -4.291 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.421 | Likely Benign | -0.84 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.60 | Benign | 0.44 | Tolerated | 0.2602 | 0.1854 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||||||||||
| c.3586A>C | K1196Q 2D AIThe SynGAP1 missense variant K1196Q is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default 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 Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of benign predictions and the lack of pathogenic evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -5.222 | Likely Benign | 0.346 | Ambiguous | Likely Benign | 0.342 | Likely Benign | -0.65 | Neutral | 0.989 | Probably Damaging | 0.819 | Possibly Damaging | 5.38 | Benign | 0.07 | Tolerated | 0.3814 | 0.0945 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3586A>G | K1196E 2D AIThe SynGAP1 missense variant K1196E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools are divided: benign predictions come from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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, 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 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 Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -6.382 | Likely Benign | 0.734 | Likely Pathogenic | Likely Benign | 0.358 | Likely Benign | -0.02 | Neutral | 0.961 | Probably Damaging | 0.764 | Possibly Damaging | 5.38 | Benign | 0.42 | Tolerated | 0.3272 | 0.0720 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3587A>G | K1196R 2D AIThe SynGAP1 missense variant K1196R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, and the SGM‑Consensus score is “Likely Benign.” No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.435699 | Uncertain | 0.851 | 0.595 | 0.250 | -2.077 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.78 | Neutral | 0.031 | Benign | 0.047 | Benign | 5.39 | Benign | 0.53 | Tolerated | 0.3970 | 0.0721 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.3589G>A | E1197K 2D AIThe SynGAP1 E1197K missense change is not reported in ClinVar and has no gnomAD entry. Functional prediction tools that agree on benign impact include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus (SGM‑Consensus) classifies the variant as Likely Benign, whereas AlphaMissense‑Optimized predicts it to be Pathogenic; Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a benign effect, though the single high‑accuracy pathogenic prediction introduces uncertainty. The variant is most likely benign based on the current predictions, 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 | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -5.048 | Likely Benign | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.364 | Likely Benign | -0.27 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.45 | Benign | 0.45 | Tolerated | 0.1512 | 0.5424 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3589G>C | E1197Q 2D AIThe SynGAP1 missense variant E1197Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and no Foldetta stability data are available. Overall, the balance of evidence favors a benign interpretation, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -2.771 | Likely Benign | 0.692 | Likely Pathogenic | Likely Benign | 0.304 | Likely Benign | -0.60 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.44 | Benign | 0.29 | Tolerated | 0.0690 | 0.5265 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.358G>A | G120S 2D  AIThe SynGAP1 missense variant G120S is reported in gnomAD (variant ID 6-33432223‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the evidence strongly supports a benign classification, and there is 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 Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | 6-33432223-G-A | 1 | 6.20e-7 | -3.558 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.034 | Likely Benign | 0.07 | Neutral | 0.020 | Benign | 0.012 | Benign | 4.29 | Benign | 0.91 | Tolerated | 3.61 | 5 | 0.2841 | 0.4713 | 0 | 1 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.358G>C | G120R 2D  AIThe SynGAP1 missense variant G120R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only AlphaMissense‑Default predicts a pathogenic outcome. When predictions are grouped, the benign consensus includes eight tools, whereas the pathogenic consensus contains a single tool. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a likely benign classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that G120R 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 | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -4.406 | Likely Benign | 0.745 | Likely Pathogenic | Likely Benign | 0.022 | Likely Benign | -0.33 | Neutral | 0.089 | Benign | 0.047 | Benign | 4.26 | Benign | 0.14 | Tolerated | 0.1050 | 0.4345 | -3 | -2 | -4.1 | 99.14 | |||||||||||||||||||||||||||||||||||||||
| c.358G>T | G120C 2D  AIThe SynGAP1 missense variant G120C is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -5.979 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.73 | Neutral | 0.410 | Benign | 0.146 | Benign | 4.20 | Benign | 0.10 | Tolerated | 0.1376 | 0.4225 | -3 | -3 | 2.9 | 46.09 | |||||||||||||||||||||||||||||||||||||||
| c.3590A>C | E1197A 2D AIThe SynGAP1 missense variant E1197A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments are less definitive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta results are unavailable. Consequently, the evidence is balanced between benign and pathogenic predictions, with no high‑confidence support for either outcome. The variant is most likely benign based on the current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -4.852 | Likely Benign | 0.795 | Likely Pathogenic | Ambiguous | 0.442 | Likely Benign | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.45 | Benign | 0.09 | Tolerated | 0.2811 | 0.5169 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3591G>C | E1197D 2D AIThe SynGAP1 missense variant E1197D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote) also indicates benign. Foldetta stability analysis is unavailable for this residue. Overall, the balance of evidence favors a benign effect for E1197D, and this conclusion does not conflict with any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -5.158 | Likely Benign | 0.776 | Likely Pathogenic | Likely Benign | 0.348 | Likely Benign | -1.78 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.41 | Benign | 0.16 | Tolerated | 0.1327 | 0.3535 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3591G>T | E1197D 2D AIThe SynGAP1 missense variant E1197D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome (3 benign vs. 1 pathogenic). High‑accuracy tools give the following results: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) predicts benign; Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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 Benign | Coiled-coil | 0.613573 | Disordered | 0.437361 | Uncertain | 0.827 | 0.599 | 0.250 | -5.158 | Likely Benign | 0.776 | Likely Pathogenic | Likely Benign | 0.348 | Likely Benign | -1.78 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 5.41 | Benign | 0.16 | Tolerated | 0.1327 | 0.3535 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3592T>A | Y1198N 2D AIThe SynGAP1 missense variant Y1198N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is “Likely Pathogenic,” and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.626927 | Disordered | 0.439379 | Uncertain | 0.853 | 0.593 | 0.250 | -13.134 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.282 | Likely Benign | -5.92 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.44 | Pathogenic | 0.26 | Tolerated | 0.2093 | 0.0373 | -2 | -2 | -2.2 | -49.07 | ||||||||||||||||||||||||||||||||||||||
| c.3592T>C | Y1198H 2D AIThe SynGAP1 missense variant Y1198H 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 SIFT, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic impact. High‑accuracy assessments further support this: 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 no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.626927 | Disordered | 0.439379 | Uncertain | 0.853 | 0.593 | 0.250 | -10.394 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.246 | Likely Benign | -2.86 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.45 | Pathogenic | 0.19 | Tolerated | 0.1975 | 0.0373 | 0 | 2 | -1.9 | -26.03 | ||||||||||||||||||||||||||||||||||||||
| c.3592T>G | Y1198D 2D AIThe SynGAP1 missense variant Y1198D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely pathogenic effect. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools suggests that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.626927 | Disordered | 0.439379 | Uncertain | 0.853 | 0.593 | 0.250 | -14.709 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.325 | Likely Benign | -6.61 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.44 | Pathogenic | 0.18 | Tolerated | 0.4310 | 0.0373 | -4 | -3 | -2.2 | -48.09 | ||||||||||||||||||||||||||||||||||||||
| c.3593A>C | Y1198S 2D AIThe SynGAP1 missense variant Y1198S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.626927 | Disordered | 0.439379 | Uncertain | 0.853 | 0.593 | 0.250 | -13.252 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.398 | Likely Benign | -5.88 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.45 | Pathogenic | 0.38 | Tolerated | 0.4901 | 0.1043 | -3 | -2 | 0.5 | -76.10 | ||||||||||||||||||||||||||||||||||||||
| c.3593A>G | Y1198C 2D AIThe SynGAP1 missense variant Y1198C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.626927 | Disordered | 0.439379 | Uncertain | 0.853 | 0.593 | 0.250 | -10.230 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.370 | Likely Benign | -6.07 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.43 | Pathogenic | 0.07 | Tolerated | 0.3335 | 0.1312 | 0 | -2 | 3.8 | -60.04 | ||||||||||||||||||||||||||||||||||||||
| c.3593A>T | Y1198F 2D AIThe SynGAP1 missense variant Y1198F is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools—ESM1b and AlphaMissense‑Optimized—return uncertain results. High‑accuracy assessments further support a deleterious effect: the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels the variant as Likely Pathogenic, and AlphaMissense‑Optimized remains uncertain; Foldetta, a protein‑folding stability method, has no available output for this variant. Overall, the preponderance of evidence (five pathogenic vs. two benign predictions) indicates that the variant is most likely pathogenic, 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. | Likely Pathogenic | Coiled-coil | 0.626927 | Disordered | 0.439379 | Uncertain | 0.853 | 0.593 | 0.250 | -7.508 | In-Between | 0.853 | Likely Pathogenic | Ambiguous | 0.219 | Likely Benign | -2.87 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.55 | Pathogenic | 0.13 | Tolerated | 0.1780 | 0.2571 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3598G>A | E1200K 2D AIThe SynGAP1 missense variant E1200K is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign effect, with no conflict with ClinVar status (which has no entry). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.545602 | Disordered | 0.458056 | Uncertain | 0.889 | 0.596 | 0.250 | -6.489 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -1.05 | Neutral | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 2.71 | Benign | 0.19 | Tolerated | 0.1690 | 0.4551 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3598G>C | E1200Q 2D AIThe SynGAP1 missense variant E1200Q is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, 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) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available, so these do not influence the overall interpretation. High‑accuracy assessments—AlphaMissense‑Optimized (benign) and SGM‑Consensus (likely benign)—support a benign classification. Consequently, the variant is most likely benign, 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 Benign | Coiled-coil | 0.545602 | Disordered | 0.458056 | Uncertain | 0.889 | 0.596 | 0.250 | -4.411 | Likely Benign | 0.464 | Ambiguous | Likely Benign | 0.183 | Likely Benign | 0.14 | Neutral | 0.994 | Probably Damaging | 0.946 | Probably Damaging | 2.84 | Benign | 0.30 | Tolerated | 0.0767 | 0.4012 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.359G>A | G120D 2D  AIThe SynGAP1 missense variant G120D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is 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 evidence overwhelmingly supports a benign classification, 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 | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -3.483 | Likely Benign | 0.465 | Ambiguous | Likely Benign | 0.037 | Likely Benign | -0.57 | Neutral | 0.165 | Benign | 0.034 | Benign | 4.25 | Benign | 0.21 | Tolerated | 0.1847 | 0.2024 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.359G>C | G120A 2D  AIThe SynGAP1 missense variant G120A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -3.477 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.29 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.37 | Benign | 1.00 | Tolerated | 0.4003 | 0.4565 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.359G>T | G120V 2D  AIThe SynGAP1 missense variant G120V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is not contradicted by any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.659993 | Binding | 0.359 | 0.887 | 0.750 | -4.571 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.68 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.28 | Benign | 0.19 | Tolerated | 0.1321 | 0.3883 | -1 | -3 | 4.6 | 42.08 | |||||||||||||||||||||||||||||||||||||||
| c.3603G>C | E1201D 2D AIThe SynGAP1 missense variant E1201D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, and SIFT, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic classification. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the preponderance of evidence points to 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 | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -8.727 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.150 | Likely Benign | -1.55 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.66 | Pathogenic | 0.51 | Tolerated | 0.1341 | 0.3335 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3603G>T | E1201D 2D AIThe SynGAP1 missense variant E1201D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, PROVEAN, and SIFT, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy consensus methods reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely pathogenic classification. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the preponderance of evidence points to 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 | Coiled-coil | 0.525368 | Disordered | 0.481868 | Uncertain | 0.870 | 0.596 | 0.250 | -8.727 | Likely Pathogenic | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.150 | Likely Benign | -1.55 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.66 | Pathogenic | 0.51 | Tolerated | 0.1341 | 0.3335 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3604A>C | I1202L 2D  AIThe SynGAP1 I1202L missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, and SIFT, whereas those that predict a pathogenic impact are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) remains Likely Pathogenic; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion is not contradicted by 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 | Coiled-coil | 0.529623 | Disordered | 0.510422 | Binding | 0.874 | 0.593 | 0.250 | -8.026 | Likely Pathogenic | 0.953 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -1.27 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.94 | Pathogenic | 0.59 | Tolerated | 0.0788 | 0.2874 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.3607C>A | H1203N 2D  AIThe SynGAP1 missense variant H1203N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, and Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | -4.278 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.181 | Likely Benign | -1.07 | Neutral | 0.002 | Benign | 0.018 | Benign | 5.61 | Benign | 0.31 | Tolerated | 0.1155 | 0.0914 | 2 | 1 | -0.3 | -23.04 | ||||||||||||||||||||||||||||||||||||||
| c.3607C>G | H1203D 2D  AIThe SynGAP1 missense variant H1203D is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | Uncertain | 2 | -6.729 | Likely Benign | 0.525 | Ambiguous | Likely Benign | 0.403 | Likely Benign | -1.89 | Neutral | 0.473 | Possibly Damaging | 0.265 | Benign | 5.51 | Benign | 0.24 | Tolerated | 3.77 | 5 | 0.1926 | 0.0530 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||
| c.3607C>T | H1203Y 2D  AIThe SynGAP1 missense variant H1203Y is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33446599‑C‑T). Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign prediction. Foldetta results are unavailable. Overall, the evidence strongly supports a benign impact for H1203Y, 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 | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | Uncertain | 1 | 6-33446599-C-T | 2 | 1.24e-6 | -6.834 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.233 | Likely Benign | -1.52 | Neutral | 0.006 | Benign | 0.011 | Benign | 5.55 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.0588 | 0.2379 | 2 | 0 | 1.9 | 26.03 | |||||||||||||||||||||||||||||||
| c.3608A>C | H1203P 2D  AIThe SynGAP1 missense variant H1203P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). AlphaMissense‑Optimized predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the balance of evidence (five pathogenic vs. four benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | -11.286 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.485 | Likely Benign | -2.10 | Neutral | 0.975 | Probably Damaging | 0.767 | Possibly Damaging | 5.47 | Benign | 0.26 | Tolerated | 0.1742 | 0.2820 | 0 | -2 | 1.6 | -40.02 | |||||||||||||||||||||||||||||||||||||||
| c.3608A>G | H1203R 2D  AIThe SynGAP1 missense variant H1203R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv 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 further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | -3.355 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.287 | Likely Benign | -1.61 | Neutral | 0.473 | Possibly Damaging | 0.265 | Benign | 5.51 | Benign | 0.20 | Tolerated | 0.1263 | 0.1178 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||||
| c.3608A>T | H1203L 2D  AIThe SynGAP1 missense variant H1203L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | -4.179 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 0.361 | Likely Benign | -2.23 | Neutral | 0.473 | Possibly Damaging | 0.265 | Benign | 5.53 | Benign | 0.21 | Tolerated | 0.0682 | 0.2951 | -2 | -3 | 7.0 | -23.98 | ||||||||||||||||||||||||||||||||||||||
| c.3609C>A | H1203Q 2D  AIThe SynGAP1 missense variant H1203Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates “Likely Benign.” In contrast, the two polyPhen‑2 classifiers (HumDiv and HumVar) predict pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus remains “Likely Benign.” Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H1203Q, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | -1.924 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.233 | Likely Benign | -1.35 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 5.54 | Benign | 0.17 | Tolerated | 0.0974 | 0.1581 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3609C>G | H1203Q 2D AIThe SynGAP1 missense variant H1203Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates “Likely Benign.” In contrast, the two polyPhen‑2 classifiers (HumDiv and HumVar) predict pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus remains “Likely Benign.” Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for H1203Q, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.618285 | Disordered | 0.527023 | Binding | 0.892 | 0.589 | 0.250 | -1.924 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.233 | Likely Benign | -1.35 | Neutral | 0.642 | Possibly Damaging | 0.494 | Possibly Damaging | 5.54 | Benign | 0.17 | Tolerated | 0.0974 | 0.1581 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3610T>A | S1204T 2D AIThe SynGAP1 missense variant S1204T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates “Likely Benign.” In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are unavailable, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar classification (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.595080 | Disordered | 0.541098 | Binding | 0.887 | 0.587 | 0.375 | -5.056 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.292 | Likely Benign | -0.53 | Neutral | 0.826 | Possibly Damaging | 0.551 | Possibly Damaging | 5.42 | Benign | 0.94 | Tolerated | 0.1466 | 0.4510 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3610T>C | S1204P 2D AIThe SynGAP1 missense variant S1204P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S1204P. This prediction does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.595080 | Disordered | 0.541098 | Binding | 0.887 | 0.587 | 0.375 | -14.031 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.502 | Likely Pathogenic | -1.80 | Neutral | 0.988 | Probably Damaging | 0.856 | Possibly Damaging | 5.39 | Benign | 0.31 | Tolerated | 0.2139 | 0.3886 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3610T>G | S1204A 2D AIThe SynGAP1 missense variant S1204A is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective evidence, the variant is most likely 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 | Coiled-coil | 0.595080 | Disordered | 0.541098 | Binding | 0.887 | 0.587 | 0.375 | -5.134 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.213 | Likely Benign | -0.53 | Neutral | 0.061 | Benign | 0.047 | Benign | 5.45 | Benign | 1.00 | Tolerated | 0.4943 | 0.3167 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3611C>T | S1204L 2D AIThe SynGAP1 missense variant S1204L is reported in gnomAD (variant ID 6‑33446603‑C‑T) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool in the dataset predicts a pathogenic outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, 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 Benign | Coiled-coil | 0.595080 | Disordered | 0.541098 | Binding | 0.887 | 0.587 | 0.375 | 6-33446603-C-T | 1 | 6.20e-7 | -4.672 | Likely Benign | 0.325 | Likely Benign | Likely Benign | 0.375 | Likely Benign | -0.86 | Neutral | 0.035 | Benign | 0.028 | Benign | 5.35 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.1000 | 0.4082 | -2 | -3 | 4.6 | 26.08 | |||||||||||||||||||||||||||||||||
| c.3616A>C | K1206Q 2D AIThe SynGAP1 K1206Q missense change is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, SIFT, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta data are unavailable. Consequently, the evidence is evenly split between benign and pathogenic interpretations. The variant therefore falls into a category of uncertain significance, with no conflict with the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.585406 | Disordered | 0.555819 | Binding | 0.893 | 0.569 | 0.375 | -8.654 | Likely Pathogenic | 0.817 | Likely Pathogenic | Ambiguous | 0.130 | Likely Benign | -0.92 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.65 | Benign | 0.49 | Tolerated | 0.3829 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3617A>G | K1206R 2D AIThe SynGAP1 missense variant K1206R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. AlphaMissense‑Default is uncertain, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it receives two benign, one pathogenic, and one uncertain signal. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy AlphaMissense‑Optimized predicts a benign effect, while Foldetta data are missing. Overall, the majority of evidence points to a benign 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. | Coiled-coil | 0.585406 | Disordered | 0.555819 | Binding | 0.893 | 0.569 | 0.375 | -6.357 | Likely Benign | 0.371 | Ambiguous | Likely Benign | 0.126 | Likely Benign | -1.64 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.49 | Pathogenic | 0.07 | Tolerated | 0.3897 | 0.0945 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.361G>T | A121S 2D  AIThe SynGAP1 missense variant A121S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods also support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | -3.027 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.06 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.18 | Benign | 0.40 | Tolerated | 0.2805 | 0.5817 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3621G>C | E1207D 2D AIThe SynGAP1 missense variant E1207D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all classify the change as tolerated or benign. Only FATHMM predicts a pathogenic outcome. High‑accuracy tools that were available give a benign verdict: AlphaMissense‑Optimized is benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign. Foldetta results are not reported, so they do not influence the assessment. Overall, the majority of evidence supports a benign interpretation, and this is consistent with the lack of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -3.924 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.010 | Likely Benign | -1.16 | Neutral | 0.121 | Benign | 0.069 | Benign | 2.26 | Pathogenic | 0.51 | Tolerated | 0.1485 | 0.2810 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3621G>T | E1207D 2D AIThe SynGAP1 missense variant E1207D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only FATHMM predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus 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 consensus of the majority of tools, including the high‑accuracy predictors, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.604312 | Disordered | 0.562696 | Binding | 0.912 | 0.571 | 0.375 | -3.924 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.010 | Likely Benign | -1.16 | Neutral | 0.121 | Benign | 0.069 | Benign | 2.26 | Pathogenic | 0.51 | Tolerated | 0.1485 | 0.2810 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3629A>G | H1210R 2D AIThe SynGAP1 missense variant H1210R is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments corroborate this benign consensus: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields “Likely Benign.” Foldetta results are not available, so they do not influence the interpretation. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.587579 | Binding | 0.900 | 0.567 | 0.375 | 0.860 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.89 | Neutral | 0.178 | Benign | 0.089 | Benign | 3.25 | Benign | 1.00 | Tolerated | 0.1535 | 0.2384 | 2 | 0 | -1.3 | 19.05 | ||||||||||||||||||||||||||||||||||||||
| c.362C>G | A121G 2D  AIThe SynGAP1 missense variant A121G is catalogued in gnomAD (ID 6‑33432227‑C‑G) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the evidence strongly supports a benign effect for A121G, 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 | 0.779859 | Disordered | 0.661304 | Binding | 0.362 | 0.888 | 0.750 | 6-33432227-C-G | 4 | 2.48e-6 | -3.123 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.073 | Likely Benign | -0.52 | Neutral | 0.118 | Benign | 0.026 | Benign | 4.06 | Benign | 0.07 | Tolerated | 3.61 | 5 | 0.2407 | 0.5271 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3630C>A | H1210Q 2D AIThe SynGAP1 missense variant H1210Q is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates a benign likelihood. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of the available predictions indicates that H1210Q is most likely benign, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.587579 | Binding | 0.900 | 0.567 | 0.375 | -1.917 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.83 | Neutral | 0.512 | Possibly Damaging | 0.223 | Benign | 2.74 | Benign | 0.09 | Tolerated | 0.1133 | 0.3092 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3630C>G | H1210Q 2D AIThe SynGAP1 missense variant H1210Q is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv 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 further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.599170 | Disordered | 0.587579 | Binding | 0.900 | 0.567 | 0.375 | -1.917 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.83 | Neutral | 0.512 | Possibly Damaging | 0.223 | Benign | 2.74 | Benign | 0.09 | Tolerated | 0.1133 | 0.3092 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3631A>C | M1211L 2D AIThe SynGAP1 missense variant M1211L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Overall, the preponderance of evidence indicates that M1211L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -2.552 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.442 | Likely Benign | -0.76 | Neutral | 0.856 | Possibly Damaging | 0.881 | Possibly Damaging | 5.45 | Benign | 0.14 | Tolerated | 0.1280 | 0.3547 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3631A>G | M1211V 2D AIThe SynGAP1 missense variant M1211V is listed in ClinVar as Benign (ClinVar ID 3674914.0) and is present in gnomAD (ID 6‑33446623‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and not contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | Benign | 1 | 6-33446623-A-G | 3 | 1.86e-6 | -2.101 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.412 | Likely Benign | -0.29 | Neutral | 0.932 | Possibly Damaging | 0.949 | Probably Damaging | 5.43 | Benign | 0.72 | Tolerated | 3.77 | 5 | 0.2676 | 0.2720 | 1 | 2 | 2.3 | -32.06 | |||||||||||||||||||||||||||||||
| c.3631A>T | M1211L 2D AIThe SynGAP1 missense variant M1211L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -2.552 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.442 | Likely Benign | -0.76 | Neutral | 0.856 | Possibly Damaging | 0.881 | Possibly Damaging | 5.45 | Benign | 0.14 | Tolerated | 0.1280 | 0.3547 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3633G>A | M1211I 2D AIThe SynGAP1 missense variant M1211I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33446625-G-A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are AlphaMissense‑Default, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy predictions therefore point to a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | Uncertain | 1 | 6-33446625-G-A | 3 | 1.86e-6 | -1.537 | Likely Benign | 0.764 | Likely Pathogenic | Likely Benign | 0.298 | Likely Benign | -0.42 | Neutral | 0.969 | Probably Damaging | 0.968 | Probably Damaging | 5.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1214 | 0.2839 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||
| c.3633G>C | M1211I 2D AIThe SynGAP1 missense variant M1211I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized 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 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 Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -1.537 | Likely Benign | 0.764 | Likely Pathogenic | Likely Benign | 0.298 | Likely Benign | -0.42 | Neutral | 0.969 | Probably Damaging | 0.968 | Probably Damaging | 5.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1214 | 0.2839 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.3633G>T | M1211I 2D AIThe SynGAP1 missense variant M1211I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default 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 (three benign votes versus one pathogenic). High‑accuracy assessment by AlphaMissense‑Optimized confirms a benign prediction, whereas the Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign effect for M1211I, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.578388 | Binding | 0.876 | 0.565 | 0.500 | -1.537 | Likely Benign | 0.764 | Likely Pathogenic | Likely Benign | 0.298 | Likely Benign | -0.42 | Neutral | 0.969 | Probably Damaging | 0.968 | Probably Damaging | 5.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1214 | 0.2839 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||
| c.3637A>G | N1213D 2D  AIThe SynGAP1 missense variant N1213D is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta results are unavailable. Overall, the evidence leans toward a benign interpretation, and this conclusion does not contradict the ClinVar status, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | -9.021 | Likely Pathogenic | 0.670 | Likely Pathogenic | Likely Benign | 0.071 | Likely Benign | -1.63 | Neutral | 0.959 | Probably Damaging | 0.629 | Possibly Damaging | 2.71 | Benign | 0.07 | Tolerated | 0.1417 | 0.2174 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3638A>C | N1213T 2D  AIThe SynGAP1 missense variant N1213T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33446630‑A‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, 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 | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | Conflicting | 2 | 6-33446630-A-C | 46 | 2.85e-5 | -5.428 | Likely Benign | 0.266 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -1.08 | Neutral | 0.959 | Probably Damaging | 0.721 | Possibly Damaging | 2.74 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0968 | 0.4546 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||||
| c.3638A>G | N1213S 2D  AIThe SynGAP1 missense variant N1213S is listed in ClinVar as Benign (ClinVar ID 708250.0) and is present in the gnomAD database (gnomAD ID 6‑33446630‑A‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, PolyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, aligning with the ClinVar classification and indicating no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | Benign | 1 | 6-33446630-A-G | 13 | 8.05e-6 | -4.086 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -0.56 | Neutral | 0.906 | Possibly Damaging | 0.551 | Possibly Damaging | 2.82 | Benign | 0.68 | Tolerated | 3.77 | 5 | 0.2607 | 0.4591 | 1 | 1 | 2.7 | -27.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||
| c.3644A>G | K1215R 2D AIThe SynGAP1 missense variant K1215R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy methods reinforce the benign prediction: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign, with no Foldetta data to contradict. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.497853 | Structured | 0.503613 | Binding | 0.888 | 0.568 | 0.375 | -5.652 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.106 | Likely Benign | -0.57 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.85 | Benign | 0.28 | Tolerated | 0.4051 | 0.0582 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||||||||||
| c.364C>A | P122T 2D  AIThe SynGAP1 missense variant P122T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that P122T is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -3.954 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.186 | Likely Benign | -1.43 | Neutral | 0.580 | Possibly Damaging | 0.185 | Benign | 4.19 | Benign | 0.13 | Tolerated | 0.2068 | 0.5270 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.364C>G | P122A 2D  AIThe SynGAP1 missense variant P122A is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | -3.105 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -1.66 | Neutral | 0.363 | Benign | 0.096 | Benign | 4.27 | Benign | 1.00 | Tolerated | 0.3991 | 0.4286 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.364C>T | P122S 2D  AIThe SynGAP1 missense variant P122S is catalogued in gnomAD (ID 6‑33432229‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.672358 | Binding | 0.400 | 0.887 | 0.750 | 6-33432229-C-T | 1 | 6.20e-7 | -3.389 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -1.13 | Neutral | 0.036 | Benign | 0.025 | Benign | 4.22 | Benign | 0.31 | Tolerated | 3.61 | 5 | 0.4009 | 0.4759 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3661C>G | R1221G 2D  AIThe SynGAP1 missense variant R1221G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Two tools—ESM1b 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) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the majority of available predictions lean toward a benign impact, with no ClinVar evidence contradicting this assessment. 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. | Coiled-coil | 0.690604 | Disordered | 0.430363 | Uncertain | 0.906 | 0.539 | 0.375 | -7.982 | In-Between | 0.552 | Ambiguous | Likely Benign | 0.168 | Likely Benign | -3.55 | Deleterious | 0.992 | Probably Damaging | 0.900 | Possibly Damaging | 2.54 | Benign | 0.06 | Tolerated | 0.3185 | 0.2110 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3662G>A | R1221Q 2D AIThe SynGAP1 missense variant R1221Q is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33446654‑G‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect. 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 this: AlphaMissense‑Optimized predicts benign, SGM Consensus is likely benign, while 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, 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 | Coiled-coil | 0.690604 | Disordered | 0.430363 | Uncertain | 0.906 | 0.539 | 0.375 | Conflicting | 2 | 6-33446654-G-A | 4 | 2.48e-6 | -5.491 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.46 | Neutral | 0.836 | Possibly Damaging | 0.153 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | 0.2093 | 0.1736 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||||||||
| c.3664A>G | R1222G 2D AIThe SynGAP1 missense change R1222G is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools split into two groups: benign predictions come from REVEL and SIFT, while pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (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 evidence points to a pathogenic impact, 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 | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -11.498 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.226 | Likely Benign | -5.41 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.48 | Pathogenic | 0.10 | Tolerated | 0.3012 | 0.2305 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3665G>A | R1222K 2D AIThe SynGAP1 missense variant R1222K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized classifies the change as benign, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the SGM‑Consensus designation but contradicts the benign calls from several other predictors. Thus, based on the current computational predictions, the variant is most likely pathogenic, and this assessment aligns with the lack of ClinVar reporting rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -9.148 | Likely Pathogenic | 0.689 | Likely Pathogenic | Likely Benign | 0.249 | Likely Benign | -2.05 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.57 | Pathogenic | 0.54 | Tolerated | 0.3714 | 0.2611 | 3 | 2 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||||||
| c.3665G>C | R1222T 2D  AIThe SynGAP1 missense variant R1222T is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect are REVEL and SIFT, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that R1222T is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -11.164 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.407 | Likely Benign | -4.39 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.48 | Pathogenic | 0.13 | Tolerated | 0.1550 | 0.2851 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||
| c.3665G>T | R1222M 2D  AIThe SynGAP1 missense variant R1222M is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is “Likely Pathogenic,” and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -12.190 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 0.398 | Likely Benign | -4.11 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.46 | Pathogenic | 0.20 | Tolerated | 0.1069 | 0.2559 | 0 | -1 | 6.4 | -24.99 | ||||||||||||||||||||||||||||||||||||||
| c.3666G>C | R1222S 2D  AIThe SynGAP1 missense variant R1222S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability analysis is available for this variant. Overall, the preponderance of evidence from multiple in silico tools points to a pathogenic impact, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -9.310 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.282 | Likely Benign | -4.40 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.49 | Pathogenic | 0.10 | Tolerated | 0.2951 | 0.2426 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3666G>T | R1222S 2D AIThe SynGAP1 missense variant R1222S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and SIFT, whereas the majority of other in‑silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy prediction tools 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 | Coiled-coil | 0.703578 | Disordered | 0.423869 | Uncertain | 0.895 | 0.541 | 0.250 | -9.310 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.280 | Likely Benign | -4.40 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.49 | Pathogenic | 0.10 | Tolerated | 0.2951 | 0.2426 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3670C>A | L1224M 2D AIThe SynGAP1 missense variant L1224M is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster around a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all indicate a tolerated change. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. When focusing on high‑accuracy predictors, AlphaMissense‑Optimized remains benign and the SGM‑Consensus also supports a benign outcome; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this assessment does not conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.525368 | Disordered | 0.441554 | Uncertain | 0.871 | 0.543 | 0.500 | -5.614 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -0.55 | Neutral | 0.994 | Probably Damaging | 0.925 | Probably Damaging | 2.38 | Pathogenic | 0.18 | Tolerated | 0.0660 | 0.2486 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3670C>G | L1224V 2D AIThe SynGAP1 missense variant L1224V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of 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 also indicates a benign likelihood. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence points to the variant being 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 | Coiled-coil | 0.525368 | Disordered | 0.441554 | Uncertain | 0.871 | 0.543 | 0.500 | -5.796 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.093 | Likely Benign | -1.41 | Neutral | 0.248 | Benign | 0.112 | Benign | 2.42 | Pathogenic | 0.18 | Tolerated | 0.1397 | 0.2289 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3671T>A | L1224Q 2D AIThe SynGAP1 missense variant L1224Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for L1224Q, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.525368 | Disordered | 0.441554 | Uncertain | 0.871 | 0.543 | 0.500 | -6.254 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.125 | Likely Benign | -1.87 | Neutral | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 2.40 | Pathogenic | 0.13 | Tolerated | 0.1018 | 0.0558 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3671T>C | L1224P 2D  AIThe SynGAP1 missense variant L1224P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). In silico predictors that agree on a benign effect include REVEL and SIFT, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—consistently predict a pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also 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 predictions indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.525368 | Disordered | 0.441554 | Uncertain | 0.871 | 0.543 | 0.500 | -11.727 | Likely Pathogenic | 0.981 | Likely Pathogenic | Likely Pathogenic | 0.149 | Likely Benign | -3.18 | Deleterious | 0.998 | Probably Damaging | 0.948 | Probably Damaging | 2.36 | Pathogenic | 0.07 | Tolerated | 0.3618 | 0.1053 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||
| c.3671T>G | L1224R 2D AIThe SynGAP1 missense variant L1224R is listed in ClinVar with no assertion (ClinVar status: None) and is present in the gnomAD database (ID 6‑33446663‑T‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.525368 | Disordered | 0.441554 | Uncertain | 0.871 | 0.543 | 0.500 | 6-33446663-T-G | 1 | 6.20e-7 | -7.504 | In-Between | 0.220 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.85 | Neutral | 0.989 | Probably Damaging | 0.900 | Possibly Damaging | 2.42 | Pathogenic | 0.33 | Tolerated | 3.77 | 5 | 0.1120 | 0.0558 | -2 | -3 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||
| c.3673T>A | S1225T 2D AIThe SynGAP1 missense variant S1225T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) reports likely benign; Foldetta results are not available. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -4.409 | Likely Benign | 0.057 | Likely Benign | Likely Benign | 0.216 | Likely Benign | -0.49 | Neutral | 0.003 | Benign | 0.008 | Benign | 5.50 | Benign | 0.60 | Tolerated | 0.0972 | 0.4618 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3673T>C | S1225P 2D AIThe SynGAP1 missense variant S1225P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of high‑accuracy predictors (five pathogenic vs. four benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -12.278 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.489 | Likely Benign | -2.07 | Neutral | 0.784 | Possibly Damaging | 0.575 | Possibly Damaging | 5.36 | Benign | 0.25 | Tolerated | 0.1499 | 0.4570 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3673T>G | S1225A 2D AIThe SynGAP1 missense variant S1225A is not reported in ClinVar and is absent from gnomAD, indicating no known clinical annotation or population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -3.157 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.257 | Likely Benign | -0.16 | Neutral | 0.139 | Benign | 0.089 | Benign | 5.51 | Benign | 1.00 | Tolerated | 0.3804 | 0.3823 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3674C>G | S1225C 2D AIThe SynGAP1 missense variant S1225C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict 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 interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta results are not available for this variant. Overall, the preponderance of evidence indicates that S1225C 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 | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -6.494 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.306 | Likely Benign | -0.27 | Neutral | 0.975 | Probably Damaging | 0.870 | Possibly Damaging | 5.35 | Benign | 0.15 | Tolerated | 0.0669 | 0.4842 | 0 | -1 | 3.3 | 16.06 | ||||||||||||||||||||||||||||||||||||||
| c.3674C>T | S1225F 2D  AIThe SynGAP1 missense variant S1225F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S1225F, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.513880 | Disordered | 0.441915 | Uncertain | 0.891 | 0.544 | 0.500 | -7.938 | In-Between | 0.328 | Likely Benign | Likely Benign | 0.423 | Likely Benign | -2.34 | Neutral | 0.927 | Possibly Damaging | 0.690 | Possibly Damaging | 5.37 | Benign | 0.06 | Tolerated | 0.0505 | 0.4979 | -3 | -2 | 3.6 | 60.10 | ||||||||||||||||||||||||||||||||||||||
| c.367G>A | A123T 2D  AIThe SynGAP1 missense variant A123T is reported as “Likely Benign” in ClinVar and is not present in gnomAD. Prediction tools that assess functional impact all converge on a benign outcome: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign effect. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -3.999 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.117 | Likely Benign | 0.59 | Neutral | 0.004 | Benign | 0.001 | Benign | 4.29 | Benign | 0.52 | Tolerated | 0.1912 | 0.7109 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.367G>T | A123S 2D AIThe SynGAP1 missense variant A123S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions strongly supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.521092 | Disordered | 0.689505 | Binding | 0.324 | 0.886 | 0.750 | -3.309 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.03 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.21 | Benign | 0.28 | Tolerated | 0.2979 | 0.6011 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3682G>C | E1228Q 2D AIThe SynGAP1 missense variant E1228Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the computational evidence overwhelmingly supports a benign interpretation, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.517562 | Disordered | 0.447051 | Uncertain | 0.892 | 0.546 | 0.500 | -2.675 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.32 | Neutral | 0.287 | Benign | 0.112 | Benign | 2.69 | Benign | 0.25 | Tolerated | 0.0830 | 0.3797 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3685C>A | Q1229K 2D  AISynGAP1 missense variant Q1229K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign calls from REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic calls from polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessment shows AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic; Foldetta stability analysis is unavailable. Overall, the evidence is split, with an equal number of benign and pathogenic predictions, and the high‑accuracy tools provide one benign and one pathogenic call. Thus, the variant is most likely pathogenic based on the preponderance of pathogenic predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | -9.803 | Likely Pathogenic | 0.471 | Ambiguous | Likely Benign | 0.159 | Likely Benign | -2.36 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.82 | Pathogenic | 0.22 | Tolerated | 0.1347 | 0.2883 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3685C>G | Q1229E 2D  AIThe SynGAP1 missense change Q1229E lies in a coiled‑coil domain. ClinVar has no entry for this variant, and it is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; 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, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | -7.319 | In-Between | 0.274 | Likely Benign | Likely Benign | 0.204 | Likely Benign | -1.75 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 1.80 | Pathogenic | 0.17 | Tolerated | 0.1184 | 0.1336 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3686A>C | Q1229P 2D  AIThe SynGAP1 missense variant Q1229P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is “Likely Pathogenic.” No Foldetta stability prediction is available for this variant. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | Uncertain | 1 | -10.397 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.422 | Likely Benign | -3.69 | Deleterious | 0.998 | Probably Damaging | 0.995 | Probably Damaging | 1.75 | Pathogenic | 0.12 | Tolerated | 3.77 | 5 | 0.2197 | 0.4107 | 0 | -1 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||
| c.3686A>G | Q1229R 2D  AIThe SynGAP1 missense variant Q1229R is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in‑silico predictors shows a split: benign calls come from REVEL, SIFT, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic verdict. High‑accuracy assessments further illustrate this divergence: AlphaMissense‑Optimized predicts benign, while the SGM‑Consensus (majority vote) indicates pathogenic; Foldetta data are unavailable. With five tools favoring pathogenicity versus two supporting benign, the overall prediction leans toward pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | -8.998 | Likely Pathogenic | 0.518 | Ambiguous | Likely Benign | 0.282 | Likely Benign | -2.53 | Deleterious | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 1.80 | Pathogenic | 0.16 | Tolerated | 0.1178 | 0.1200 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||||
| c.3686A>T | Q1229L 2D  AIThe SynGAP1 missense variant Q1229L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into three groups: benign predictions come from REVEL, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; the remaining tools (ESM1b and AlphaMissense‑Default) are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as 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 favor a pathogenic effect, whereas the single high‑accuracy tool suggests benign. Given the lack of ClinVar evidence, the variant is most likely pathogenic according to the collective predictions, with no contradiction to existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | -7.366 | In-Between | 0.496 | Ambiguous | Likely Benign | 0.349 | Likely Benign | -4.60 | Deleterious | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 1.77 | Pathogenic | 0.09 | Tolerated | 0.0541 | 0.4253 | -2 | -2 | 7.3 | -14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3688A>T | T1230S 2D  AIThe SynGAP1 missense variant T1230S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for T1230S, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -5.974 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.405 | Likely Benign | -1.47 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 5.64 | Benign | 0.06 | Tolerated | 0.2405 | 0.3321 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3689C>G | T1230S 2D AIThe SynGAP1 missense variant T1230S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for T1230S, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -5.974 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.291 | Likely Benign | -1.47 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 5.64 | Benign | 0.06 | Tolerated | 0.2405 | 0.3321 | 1 | 1 | -0.1 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3691A>C | S1231R 2D  AIThe SynGAP1 missense variant S1231R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv 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 “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is unavailable. Overall, the balance of evidence favors a benign interpretation; 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 | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -6.862 | Likely Benign | 0.847 | Likely Pathogenic | Ambiguous | 0.108 | Likely Benign | -0.59 | Neutral | 0.801 | Possibly Damaging | 0.417 | Benign | 2.68 | Benign | 0.11 | Tolerated | 0.0709 | 0.2960 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3691A>G | S1231G 2D AIThe SynGAP1 missense variant S1231G is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. The high‑accuracy consensus, SGM‑Consensus, also reports the variant as Likely Benign, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. AlphaMissense‑Optimized independently predicts a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -5.384 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -1.78 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.66 | Benign | 0.23 | Tolerated | 0.2247 | 0.3614 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3692G>A | S1231N 2D AIThe SynGAP1 missense variant S1231N is predicted to be benign by all available in‑silico tools. Consensus predictors such as REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” status. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. ClinVar contains no entry for this variant, and it is not present in gnomAD. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -3.443 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.28 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.67 | Benign | 0.19 | Tolerated | 0.0954 | 0.3330 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||
| c.3692G>C | S1231T 2D AIThe SynGAP1 missense variant S1231T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv 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 interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S1231T 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 | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -4.166 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -1.29 | Neutral | 0.625 | Possibly Damaging | 0.252 | Benign | 2.67 | Benign | 0.31 | Tolerated | 0.1115 | 0.4579 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3693C>A | S1231R 2D AIThe SynGAP1 missense variant S1231R 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, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain, providing no clear direction. High‑accuracy assessments show the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign, while AlphaMissense‑Optimized remains uncertain; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -6.862 | Likely Benign | 0.847 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | -0.59 | Neutral | 0.801 | Possibly Damaging | 0.417 | Benign | 2.68 | Benign | 0.11 | Tolerated | 0.0709 | 0.2960 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3693C>G | S1231R 2D AIThe SynGAP1 missense variant S1231R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict 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 | Coiled-coil | 0.490133 | Structured | 0.519419 | Binding | 0.876 | 0.544 | 0.250 | -6.862 | Likely Benign | 0.847 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | -0.59 | Neutral | 0.801 | Possibly Damaging | 0.417 | Benign | 2.68 | Benign | 0.11 | Tolerated | 0.0709 | 0.2960 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||
| c.3697A>C | I1233L 2D AIThe SynGAP1 missense variant I1233L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score the substitution as benign, and AlphaMissense‑Optimized also predicts a benign outcome. No tool predicts pathogenicity; 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 corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates likely benign; Foldetta data are not available. Overall, the consensus of available predictions points to a benign effect, and this is consistent with the lack of ClinVar evidence or gnomAD observation. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -3.031 | Likely Benign | 0.382 | Ambiguous | Likely Benign | 0.113 | Likely Benign | -0.01 | Neutral | 0.211 | Benign | 0.108 | Benign | 2.95 | Benign | 1.00 | Tolerated | 0.0631 | 0.3246 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.3697A>G | I1233V 2D  AIThe SynGAP1 missense change I1233V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for I1233V, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.525368 | Disordered | 0.564054 | Binding | 0.881 | 0.531 | 0.125 | -2.826 | Likely Benign | 0.615 | Likely Pathogenic | Likely Benign | 0.036 | Likely Benign | -0.59 | Neutral | 0.437 | Benign | 0.170 | Benign | 2.79 | Benign | 0.06 | Tolerated | 0.0950 | 0.3270 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3700C>G | L1234V 2D AIThe SynGAP1 missense variant L1234V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools, AlphaMissense‑Default and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result. Overall, the balance of evidence leans toward a benign classification, and this assessment does not contradict the ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.599170 | Disordered | 0.575096 | Binding | 0.844 | 0.527 | 0.125 | -7.863 | In-Between | 0.402 | Ambiguous | Likely Benign | 0.090 | Likely Benign | -1.80 | Neutral | 0.898 | Possibly Damaging | 0.602 | Possibly Damaging | 1.54 | Pathogenic | 0.50 | Tolerated | 0.1314 | 0.2918 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3703A>C | M1235L 2D AIThe SynGAP1 missense variant M1235L is reported as “Likely Benign” by the SGM‑Consensus method and has no ClinVar entry, indicating it has not been classified in that database. It is also absent from gnomAD, so its allele frequency is not documented there. Across the spectrum of in‑silico predictors, all tools that provide a verdict—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—concur that the substitution is benign; none predict pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Based on the unanimous benign predictions and the lack of ClinVar classification, the variant is most likely benign, with no contradiction to existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -2.013 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1363 | 0.3935 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3703A>T | M1235L 2D AIThe SynGAP1 missense variant M1235L is reported as “Likely Benign” in the SGM‑Consensus and has no ClinVar entry, and it is not listed in gnomAD. All available in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar or gnomAD evidence, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.690604 | Disordered | 0.577958 | Binding | 0.872 | 0.532 | 0.125 | -2.013 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.38 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1363 | 0.3935 | 4 | 2 | 1.9 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.3706C>G | Q1236E 2D AIThe SynGAP1 missense variant Q1236E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence supports a benign classification for Q1236E, 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 | Coiled-coil | 0.680603 | Disordered | 0.567914 | Binding | 0.883 | 0.537 | 0.125 | -0.371 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.263 | Likely Benign | 0.66 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 3.18 | Benign | 1.00 | Tolerated | 0.0985 | 0.1130 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||
| c.370G>A | A124T 2D AIThe SynGAP1 missense variant A124T is reported in gnomAD (6-33432235‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, 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 predicts benign, and the SGM‑Consensus itself is 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 | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | 6-33432235-G-A | 1 | 6.20e-7 | -3.551 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.26 | Neutral | 0.734 | Possibly Damaging | 0.187 | Benign | 4.17 | Benign | 0.78 | Tolerated | 3.61 | 5 | 0.1828 | 0.7680 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.370G>T | A124S 2D AIThe SynGAP1 missense variant A124 S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates 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 reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.699139 | Binding | 0.340 | 0.883 | 0.750 | -1.933 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.35 | Neutral | 0.849 | Possibly Damaging | 0.303 | Benign | 4.22 | Benign | 0.65 | Tolerated | 0.3018 | 0.6192 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.3712C>A | Q1238K 2D AIThe SynGAP1 missense variant Q1238K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. 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. | Coiled-coil | 0.562014 | Disordered | 0.548882 | Binding | 0.855 | 0.545 | 0.250 | -8.631 | Likely Pathogenic | 0.513 | Ambiguous | Likely Benign | 0.195 | Likely Benign | -1.70 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.51 | Benign | 0.30 | Tolerated | 0.1345 | 0.3494 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3727C>A | Q1243K 2D AIThe SynGAP1 missense variant Q1243K is reported in gnomAD (6‑33446719‑C‑A) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only polyPhen‑2 HumDiv predicts a pathogenic outcome; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the variant is most likely benign, 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 Benign | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | 6-33446719-C-A | 1 | 6.20e-7 | -7.110 | In-Between | 0.230 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -1.39 | Neutral | 0.679 | Possibly Damaging | 0.446 | Benign | 2.72 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.1276 | 0.2303 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||
| c.3727C>G | Q1243E 2D AIThe SynGAP1 missense variant Q1243E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome; Foldetta results are unavailable. 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 | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | -1.439 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.88 | Neutral | 0.166 | Benign | 0.146 | Benign | 2.94 | Benign | 1.00 | Tolerated | 0.1067 | 0.0930 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||
| c.3730A>G | S1244G 2D AIThe SynGAP1 missense variant S1244G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. The SGM Consensus, derived from a majority vote of 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 evidence therefore comes only from AlphaMissense‑Optimized, which predicts benign, while the other high‑accuracy tools are unavailable. Overall, the balance of evidence (five benign vs four pathogenic predictions, with the most reliable tool indicating benign) suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.648219 | Disordered | 0.411055 | Uncertain | 0.833 | 0.549 | 0.500 | -8.304 | Likely Pathogenic | 0.221 | Likely Benign | Likely Benign | 0.130 | Likely Benign | -1.77 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.12 | Pathogenic | 0.65 | Tolerated | 0.2267 | 0.3678 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3731G>A | S1244N 2D AIThe SynGAP1 missense variant S1244N is listed in ClinVar with an “Uncertain” status (ClinVar ID 931075.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized, whereas PolyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward a pathogenic effect, which does not contradict the ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.648219 | Disordered | 0.411055 | Uncertain | 0.833 | 0.549 | 0.500 | Uncertain | 1 | -9.008 | Likely Pathogenic | 0.751 | Likely Pathogenic | Likely Benign | 0.154 | Likely Benign | -1.87 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.10 | Pathogenic | 0.15 | Tolerated | 3.77 | 5 | 0.1033 | 0.3464 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||
| c.3731G>C | S1244T 2D AISynGAP1 missense variant S1244T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on benign effect include REVEL, PROVEAN, SIFT, and AlphaMissense‑Optimized. Tools that agree on pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments give AlphaMissense‑Optimized a benign score, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the balance of evidence leans toward pathogenicity, with four high‑confidence pathogenic predictions versus four benign predictions, and the SGM Consensus tipping the scale. This conclusion does not contradict ClinVar status, as the variant has not yet been classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.648219 | Disordered | 0.411055 | Uncertain | 0.833 | 0.549 | 0.500 | -9.020 | Likely Pathogenic | 0.405 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -1.82 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.24 | Pathogenic | 0.11 | Tolerated | 0.1129 | 0.4603 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3736A>C | K1246Q 2D AIThe SynGAP1 missense change K1246Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that K1246Q is most likely benign, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -0.718 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.43 | Neutral | 0.961 | Probably Damaging | 0.721 | Possibly Damaging | 2.66 | Benign | 0.06 | Tolerated | 0.3708 | 0.0740 | 1 | 1 | 0.4 | -0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3736A>G | K1246E 2D AIThe SynGAP1 missense variant K1246E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. 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 is also likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.750527 | Disordered | 0.375382 | Uncertain | 0.887 | 0.564 | 0.625 | -2.052 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.127 | Likely Benign | 0.80 | Neutral | 0.910 | Possibly Damaging | 0.630 | Possibly Damaging | 2.89 | Benign | 1.00 | Tolerated | 0.3328 | 0.0514 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||||||||||
| c.3748C>A | Q1250K 2D AIThe SynGAP1 missense variant Q1250K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -6.804 | Likely Benign | 0.258 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.60 | Neutral | 0.985 | Probably Damaging | 0.981 | Probably Damaging | 2.81 | Benign | 0.13 | Tolerated | 0.1464 | 0.2484 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||||||||||
| c.3749A>G | Q1250R 2D AIThe SynGAP1 missense variant Q1250R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence 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 | Coiled-coil | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -5.183 | Likely Benign | 0.230 | Likely Benign | Likely Benign | 0.148 | Likely Benign | 0.76 | Neutral | 0.994 | Probably Damaging | 0.988 | Probably Damaging | 3.09 | Benign | 1.00 | Tolerated | 0.1330 | 0.0874 | 1 | 1 | -1.0 | 28.06 | ||||||||||||||||||||||||||||||||||||||
| c.374C>G | P125R 2D  AIThe SynGAP1 missense variant P125R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta data are unavailable. Consequently, the overall computational evidence is split evenly between benign and pathogenic predictions, with no decisive support from the most accurate methods. Based on these predictions, the variant’s impact remains inconclusive; it is neither clearly benign nor pathogenic, and this lack of consensus does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.704227 | Binding | 0.373 | 0.878 | 0.625 | -5.658 | Likely Benign | 0.792 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -4.33 | Deleterious | 0.952 | Possibly Damaging | 0.521 | Possibly Damaging | 2.83 | Benign | 0.09 | Tolerated | 0.1461 | 0.2913 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3757G>A | A1253T 2D AISynGAP1 missense variant A1253T is predicted to be benign by all evaluated in‑silico tools. The consensus group of predictors—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—uniformly classify the change as benign, with no tool indicating pathogenicity. High‑accuracy methods corroborate this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also labels the variant as likely benign. Foldetta stability analysis is unavailable. ClinVar contains no entry for this variant, and it is not present in gnomAD. Overall, the predictive evidence strongly supports a benign classification, consistent with the lack of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -4.116 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.08 | Neutral | 0.042 | Benign | 0.061 | Benign | 2.79 | Benign | 0.41 | Tolerated | 0.1016 | 0.5339 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3757G>C | A1253P 2D  AIThe SynGAP1 missense variant A1253P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign votes). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy AlphaMissense‑Optimized predicts pathogenic, while AlphaMissense‑Default also predicts pathogenic; however, the majority of tools (five benign vs. four pathogenic) lean toward a benign classification. Thus, based on the current predictions, the variant is most likely benign, and this assessment does not contradict the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -11.381 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 0.062 | Likely Benign | -0.63 | Neutral | 0.568 | Possibly Damaging | 0.352 | Benign | 2.74 | Benign | 0.26 | Tolerated | 0.1565 | 0.3514 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3757G>T | A1253S 2D AIThe SynGAP1 missense variant A1253S is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta results are unavailable. Based on the consensus of all available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -3.639 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.041 | Likely Benign | 0.05 | Neutral | 0.081 | Benign | 0.111 | Benign | 2.81 | Benign | 0.33 | Tolerated | 0.2003 | 0.4159 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3758C>A | A1253E 2D  AIThe SynGAP1 missense variant A1253E is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -1.744 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.059 | Likely Benign | 2.03 | Neutral | 0.301 | Benign | 0.209 | Benign | 3.03 | Benign | 0.98 | Tolerated | 0.0948 | 0.1704 | 0 | -1 | -5.3 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3758C>G | A1253G 2D AIThe SynGAP1 missense variant A1253G is predicted to be benign by all evaluated in silico tools. Consensus predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized uniformly indicate a benign effect. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. No Foldetta stability analysis is available for this residue. The variant is not listed in ClinVar and has no entry in gnomAD, so there is no external evidence to contradict the computational predictions. Based on the collective predictions, the variant is most likely benign, and this assessment aligns with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -4.772 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -1.23 | Neutral | 0.151 | Benign | 0.148 | Benign | 2.76 | Benign | 0.26 | Tolerated | 0.1688 | 0.3407 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3758C>T | A1253V 2D  AIThe SynGAP1 missense variant A1253V is predicted to be benign by every evaluated in‑silico tool. Benign predictions are reported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. ClinVar contains no entry for A1253V, and the variant is absent from gnomAD. Based on the unanimous benign predictions and lack of conflicting evidence, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.661982 | Disordered | 0.391377 | Uncertain | 0.881 | 0.550 | 0.750 | -4.706 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.057 | Likely Benign | 0.20 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.85 | Benign | 1.00 | Tolerated | 0.0784 | 0.4473 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||
| c.3762G>C | E1254D 2D AIThe SynGAP1 missense change E1254D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as “Likely Benign.” In contrast, only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Overall, the majority of evidence indicates that E1254D 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 | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -4.648 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.44 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.62 | Benign | 0.51 | Tolerated | 0.1402 | 0.3471 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3762G>T | E1254D 2D AIThe SynGAP1 missense change E1254D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that E1254D 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 | Coiled-coil | 0.657645 | Disordered | 0.403242 | Uncertain | 0.886 | 0.555 | 0.625 | -4.648 | Likely Benign | 0.274 | Likely Benign | Likely Benign | 0.112 | Likely Benign | -0.44 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.62 | Benign | 0.51 | Tolerated | 0.1402 | 0.3471 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3769T>A | S1257T 2D AIThe SynGAP1 missense variant S1257T is predicted to be benign by all available in‑silico tools. Consensus predictors such as REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. ClinVar contains no entry for this variant, and it is not listed in gnomAD. 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 | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -5.034 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.01 | Neutral | 0.051 | Benign | 0.027 | Benign | 2.61 | Benign | 0.25 | Tolerated | 0.1034 | 0.4767 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3769T>C | S1257P 2D AIThe SynGAP1 missense variant S1257P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus as likely pathogenic; Foldetta results are unavailable. Overall, the majority of computational 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 | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -11.985 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.150 | Likely Benign | -2.54 | Deleterious | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.55 | Benign | 0.06 | Tolerated | 0.1656 | 0.4519 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||
| c.3769T>G | S1257A 2D AIThe SynGAP1 missense variant S1257A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports a benign likelihood. Foldetta results are unavailable, so they do not influence the conclusion. Overall, the preponderance of evidence points to a benign impact for S1257A, and this assessment is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -3.937 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.02 | Neutral | 0.454 | Possibly Damaging | 0.266 | Benign | 2.64 | Benign | 0.26 | Tolerated | 0.4083 | 0.3800 | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3770C>T | S1257F 2D AIThe SynGAP1 missense variant S1257F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors a benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.541878 | Disordered | 0.482380 | Uncertain | 0.889 | 0.572 | 0.375 | -8.584 | Likely Pathogenic | 0.379 | Ambiguous | Likely Benign | 0.141 | Likely Benign | -2.41 | Neutral | 0.966 | Probably Damaging | 0.837 | Possibly Damaging | 2.55 | Benign | 0.08 | Tolerated | 0.0453 | 0.4747 | -3 | -2 | 3.6 | 60.10 | |||||||||||||||||||||||||||||||||||||||
| c.3775A>C | I1259L 2D AIThe SynGAP1 missense variant I1259L is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for I1259L, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -5.822 | Likely Benign | 0.770 | Likely Pathogenic | Likely Benign | 0.152 | Likely Benign | -0.01 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 2.80 | Benign | 0.18 | Tolerated | 0.0639 | 0.3078 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||||||||||
| c.3775A>G | I1259V 2D AIThe SynGAP1 I1259V missense change is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic 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 “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | -3.670 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.171 | Likely Benign | -0.28 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 2.67 | Benign | 0.08 | Tolerated | 0.0957 | 0.2902 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3777C>G | I1259M 2D  AIThe SynGAP1 missense variant I1259M is catalogued in gnomAD (ID 6‑33446769‑C‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score, whereas PolyPhen‑2 (HumDiv and HumVar) classify the change as pathogenic. The high‑accuracy AlphaMissense‑Optimized tool reports a benign effect, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this assessment 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 | Coiled-coil | 0.494003 | Structured | 0.576405 | Binding | 0.885 | 0.574 | 0.250 | 6-33446769-C-G | 2 | 1.24e-6 | -5.177 | Likely Benign | 0.447 | Ambiguous | Likely Benign | 0.227 | Likely Benign | 1.35 | Neutral | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.0576 | 0.2358 | 1 | 2 | -2.6 | 18.03 | |||||||||||||||||||||||||||||||||
| c.3781A>G | S1261G 2D AIThe SynGAP1 missense variant S1261G 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), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates benign; Foldetta results are not available. Overall, the majority of evidence supports a benign impact for S1261G, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -5.042 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.46 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.32 | Pathogenic | 0.65 | Tolerated | 0.2063 | 0.3477 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3782G>A | S1261N 2D AIThe SynGAP1 missense variant S1261N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports 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 S1261N, 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 | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.850 | Likely Benign | 0.294 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.92 | Neutral | 0.959 | Probably Damaging | 0.551 | Possibly Damaging | 2.23 | Pathogenic | 0.12 | Tolerated | 0.0917 | 0.2820 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||
| c.3782G>C | S1261T 2D AIThe SynGAP1 missense variant S1261T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic impact. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports 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 S1261T, 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 | Coiled-coil | 0.501700 | Disordered | 0.671500 | Binding | 0.889 | 0.574 | 0.250 | -4.800 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.109 | Likely Benign | -2.01 | Neutral | 0.906 | Possibly Damaging | 0.629 | Possibly Damaging | 2.27 | Pathogenic | 0.11 | Tolerated | 0.1007 | 0.4249 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3790G>A | G1264S 2D AIThe SynGAP1 missense variant G1264S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: benign predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: 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. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -0.797 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.147 | Likely Benign | 0.82 | Neutral | 0.062 | Benign | 0.033 | Benign | 2.94 | Benign | 1.00 | Tolerated | 0.2376 | 0.4256 | 1 | 0 | -0.4 | 30.03 | ||||||||||||||||||||||||||||||||||||||
| c.3790G>C | G1264R 2D AIThe SynGAP1 missense variant G1264R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those predicting a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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, 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 the variant being 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 | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -4.482 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.094 | Likely Benign | -1.82 | Neutral | 0.934 | Possibly Damaging | 0.541 | Possibly Damaging | 2.73 | Benign | 0.09 | Tolerated | 0.0861 | 0.3860 | -3 | -2 | -4.1 | 99.14 | ||||||||||||||||||||||||||||||||||||||
| c.3790G>T | G1264C 2D AIThe SynGAP1 missense variant G1264C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence supports a benign classification for G1264C, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -5.666 | Likely Benign | 0.280 | Likely Benign | Likely Benign | 0.122 | Likely Benign | -1.03 | Neutral | 0.997 | Probably Damaging | 0.870 | Possibly Damaging | 2.74 | Benign | 0.09 | Tolerated | 0.1087 | 0.3691 | -3 | -3 | 2.9 | 46.09 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>A | G1264D 2D AIThe SynGAP1 missense variant G1264D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while only AlphaMissense‑Default predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is also 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 | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -4.725 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | 0.097 | Likely Benign | -1.29 | Neutral | 0.012 | Benign | 0.011 | Benign | 2.72 | Benign | 0.23 | Tolerated | 0.1658 | 0.1754 | 1 | -1 | -3.1 | 58.04 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>C | G1264A 2D AIThe SynGAP1 missense variant G1264A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. 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, and this conclusion is consistent with the lack of any ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -3.460 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.32 | Neutral | 0.454 | Possibly Damaging | 0.192 | Benign | 2.79 | Benign | 0.91 | Tolerated | 0.3504 | 0.4220 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3791G>T | G1264V 2D AIThe SynGAP1 missense variant G1264V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.429200 | Structured | 0.762385 | Binding | 0.897 | 0.579 | 0.000 | -6.116 | Likely Benign | 0.488 | Ambiguous | Likely Benign | 0.136 | Likely Benign | -2.33 | Neutral | 0.966 | Probably Damaging | 0.617 | Possibly Damaging | 2.74 | Benign | 0.15 | Tolerated | 0.0972 | 0.3891 | -1 | -3 | 4.6 | 42.08 | ||||||||||||||||||||||||||||||||||||||
| c.3802C>A | L1268M 2D AIThe SynGAP1 missense variant L1268M is reported in gnomAD (ID 6‑33447850‑C‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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; a Foldetta stability analysis is not available. Overall, the preponderance of evidence from multiple in silico predictors and consensus methods indicates that the variant is most likely benign, 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 Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | 6-33447850-C-A | -4.689 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.07 | Neutral | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.67 | Benign | 0.08 | Tolerated | 3.77 | 5 | 0.0627 | 0.2297 | 2 | 4 | -1.9 | 18.03 | |||||||||||||||||||||||||||||||||||
| c.3802C>G | L1268V 2D AIThe SynGAP1 missense variant L1268V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags the variant 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 view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also reports likely benign. Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for the variant, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -4.137 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.056 | Likely Benign | -0.24 | Neutral | 0.649 | Possibly Damaging | 0.157 | Benign | 2.73 | Benign | 0.25 | Tolerated | 0.1331 | 0.2289 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3803T>A | L1268Q 2D AIThe SynGAP1 missense variant L1268Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two PolyPhen‑2 implementations (HumDiv and HumVar) predict 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 reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also indicates benign. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact for this 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 Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -5.707 | Likely Benign | 0.143 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.50 | Neutral | 0.990 | Probably Damaging | 0.637 | Possibly Damaging | 2.68 | Benign | 0.08 | Tolerated | 0.0988 | 0.0558 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||
| c.3803T>C | L1268P 2D AIThe SynGAP1 missense variant L1268P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (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 high‑accuracy predictors (5 vs. 4) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -9.062 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.091 | Likely Benign | -1.03 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.65 | Benign | 0.24 | Tolerated | 0.3261 | 0.1053 | -3 | -3 | -5.4 | -16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3803T>G | L1268R 2D AIThe SynGAP1 missense change L1268R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign) all support a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy tools reinforce the benign assessment: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta results are not available, so they do not influence the interpretation. Overall, the preponderance of evidence points to a benign effect for L1268R, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.458154 | Structured | 0.804315 | Binding | 0.859 | 0.629 | 0.000 | -7.010 | In-Between | 0.293 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.79 | Neutral | 0.970 | Probably Damaging | 0.637 | Possibly Damaging | 2.68 | Benign | 0.08 | Tolerated | 0.1135 | 0.0558 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||
| c.382C>A | P128T 2D AIThe SynGAP1 missense variant P128T is listed in ClinVar with an “Uncertain” status (ClinVar ID 2801315.0) and is present in gnomAD (ID 6‑33432247‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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, 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 | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | Uncertain | 1 | 6-33432247-C-A | 1 | 6.20e-7 | -4.217 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.96 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.19 | Benign | 0.35 | Tolerated | 3.74 | 4 | 0.2023 | 0.4053 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||
| c.382C>G | P128A 2D AIThe SynGAP1 missense variant P128A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic outcome, while the SGM‑Consensus (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 also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification for P128A, 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 | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | -3.677 | Likely Benign | 0.185 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -0.64 | Neutral | 0.580 | Possibly Damaging | 0.140 | Benign | 4.21 | Benign | 0.75 | Tolerated | 0.3890 | 0.3353 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.382C>T | P128S 2D AIThe SynGAP1 missense variant P128S is reported in gnomAD (variant ID 6‑33432247‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant prediction. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, 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 | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | 6-33432247-C-T | 1 | 6.20e-7 | -3.234 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -1.35 | Neutral | 0.734 | Possibly Damaging | 0.243 | Benign | 4.20 | Benign | 0.24 | Tolerated | 3.74 | 4 | 0.3893 | 0.3697 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3832C>A | P1278T 2D AIThe SynGAP1 missense variant P1278T is catalogued in gnomAD (ID 6‑33447880‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this assessment does not contradict any ClinVar classification. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | 6-33447880-C-A | -5.505 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.60 | Neutral | 0.059 | Benign | 0.026 | Benign | 2.73 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1825 | 0.4053 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3832C>G | P1278A 2D AIThe SynGAP1 missense variant P1278A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is 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 | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.187 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.100 | Likely Benign | 0.89 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.15 | Benign | 1.00 | Tolerated | 0.3597 | 0.3353 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3832C>T | P1278S 2D AIThe SynGAP1 missense variant P1278S is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.383 | Likely Benign | 0.098 | Likely Benign | Likely Benign | 0.077 | Likely Benign | 0.28 | Neutral | 0.004 | Benign | 0.003 | Benign | 2.96 | Benign | 0.35 | Tolerated | 0.3616 | 0.3697 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3833C>T | P1278L 2D  AIThe SynGAP1 missense variant P1278L is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.806955 | Binding | 0.532 | 0.722 | 0.750 | -4.903 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.140 | Likely Benign | -1.86 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.69 | Benign | 0.07 | Tolerated | 0.2338 | 0.4996 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3835G>A | A1279T 2D AIThe SynGAP1 missense variant A1279T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33447883‑G‑A). All available in silico predictors report a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized are benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is benign; Foldetta results are not available. Overall, the computational evidence strongly supports a benign classification, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | Uncertain | 2 | 6-33447883-G-A | 2 | 1.29e-6 | -4.871 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.30 | Neutral | 0.001 | Benign | 0.000 | Benign | 2.71 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1027 | 0.5871 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||
| c.3835G>C | A1279P 2D AIThe SynGAP1 missense variant A1279P is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as benign. No tool in the dataset predicts pathogenicity. High‑accuracy consensus methods reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the collective evidence strongly suggests the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | -3.999 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.68 | Neutral | 0.299 | Benign | 0.087 | Benign | 2.67 | Benign | 0.15 | Tolerated | 0.1589 | 0.3938 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3835G>T | A1279S 2D AIThe SynGAP1 missense variant A1279S is catalogued in gnomAD (ID 6‑33447883‑G‑T) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently scores the substitution as benign. No pathogenic predictions are reported. Grouping by agreement, the benign‑predicting tools comprise the entire set, while the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | 6-33447883-G-T | -4.281 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.134 | Likely Benign | 0.37 | Neutral | 0.019 | Benign | 0.019 | Benign | 2.74 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.2166 | 0.4583 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3836C>A | A1279D 2D  AIThe SynGAP1 missense variant A1279D is catalogued in gnomAD (ID 6‑33447884‑C‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. Grouping by agreement, all available tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no result for this variant and is therefore considered 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 | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | 6-33447884-C-A | -3.914 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 1.38 | Neutral | 0.000 | Benign | 0.000 | Benign | 2.89 | Benign | 0.35 | Tolerated | 3.77 | 5 | 0.1505 | 0.2062 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3836C>G | A1279G 2D AIThe SynGAP1 missense variant A1279G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, SGM‑Consensus reports likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | -3.469 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.97 | Neutral | 0.033 | Benign | 0.017 | Benign | 2.69 | Benign | 0.19 | Tolerated | 0.1884 | 0.3473 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3836C>T | A1279V 2D AIThe SynGAP1 missense variant A1279V is reported in gnomAD (ID 6‑33447884‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions appear in the dataset, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized returns a benign score, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, has no available result for this variant. Taken together, the consensus of all available predictions is that A1279V is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.814139 | Binding | 0.485 | 0.724 | 0.750 | 6-33447884-C-T | -4.892 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -1.23 | Neutral | 0.017 | Benign | 0.017 | Benign | 2.68 | Benign | 0.07 | Tolerated | 3.77 | 5 | 0.0777 | 0.5005 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.383C>G | P128R 2D AIThe SynGAP1 missense variant P128R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls from REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. When predictions are grouped by consensus, the majority of methods (six) predict benign, while three predict pathogenic. 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 indicates a likely benign effect. Foldetta results are unavailable. Overall, the computational evidence favors a benign classification for P128R, and this conclusion is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | -5.048 | Likely Benign | 0.748 | Likely Pathogenic | Likely Benign | 0.188 | Likely Benign | -1.76 | Neutral | 0.984 | Probably Damaging | 0.601 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 0.1810 | 0.2401 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.383C>T | P128L 2D AIThe SynGAP1 missense variant P128L is catalogued in gnomAD (6‑33432248‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM‑Consensus also indicates a likely benign outcome; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is reported). Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.713069 | Binding | 0.376 | 0.878 | 0.625 | 6-33432248-C-T | 1 | 6.20e-7 | -4.791 | Likely Benign | 0.541 | Ambiguous | Likely Benign | 0.087 | Likely Benign | -0.47 | Neutral | 0.952 | Possibly Damaging | 0.500 | Possibly Damaging | 4.20 | Benign | 0.38 | Tolerated | 3.74 | 4 | 0.2548 | 0.5137 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3841G>A | A1281T 2D AIThe SynGAP1 missense variant A1281T is reported in gnomAD (6‑33447889‑G‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv 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, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the available predictions points to a benign effect, and this is not in conflict with the ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | 6-33447889-G-A | 1 | 6.44e-7 | -4.366 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.68 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 2.67 | Benign | 0.16 | Tolerated | 4.32 | 4 | 0.1479 | 0.5644 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||
| c.3841G>C | A1281P 2D AIThe SynGAP1 missense variant A1281P is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | -3.367 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.51 | Neutral | 0.149 | Benign | 0.043 | Benign | 2.64 | Benign | 0.14 | Tolerated | 0.2110 | 0.3522 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3841G>T | A1281S 2D AIThe SynGAP1 missense variant A1281S is reported in gnomAD (6‑33447889‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | 6-33447889-G-T | -4.175 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.22 | Neutral | 0.649 | Possibly Damaging | 0.266 | Benign | 2.69 | Benign | 0.33 | Tolerated | 4.32 | 4 | 0.2815 | 0.4356 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3842C>A | A1281D 2D AIThe SynGAP1 missense variant A1281D is reported in gnomAD (ID 6‑33447890‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not conflict with ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | 6-33447890-C-A | -5.183 | Likely Benign | 0.178 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.76 | Neutral | 0.901 | Possibly Damaging | 0.516 | Possibly Damaging | 2.68 | Benign | 0.15 | Tolerated | 4.32 | 4 | 0.2105 | 0.2462 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3842C>G | A1281G 2D AIThe SynGAP1 missense variant A1281G is reported as “Likely Benign” by the SGM‑Consensus tool and is absent from ClinVar and gnomAD. All standard in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) classify the change as benign, so the benign‑prediction group contains every listed tool, while no tool predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | -3.829 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.31 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.66 | Benign | 0.27 | Tolerated | 0.2382 | 0.3215 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3842C>T | A1281V 2D AIThe SynGAP1 missense variant A1281V is reported in gnomAD (ID 6‑33447890‑C‑T) and has no ClinVar entry. Across the spectrum of in silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No algorithm in the dataset returned a pathogenic or likely pathogenic label, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign status. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its influence is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.821556 | Binding | 0.434 | 0.721 | 0.875 | 6-33447890-C-T | -4.021 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.037 | Likely Benign | -0.79 | Neutral | 0.057 | Benign | 0.026 | Benign | 2.65 | Benign | 0.15 | Tolerated | 4.32 | 4 | 0.1151 | 0.4578 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.3844G>A | E1282K 2D AIThe SynGAP1 missense variant E1282K is catalogued in gnomAD (ID 6‑33447892‑G‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. Grouping by consensus, all listed tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports a benign effect for E1282K, 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 | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | 6-33447892-G-A | -3.805 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.17 | Neutral | 0.126 | Benign | 0.026 | Benign | 2.73 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.1821 | 0.5809 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||||||||
| c.3844G>C | E1282Q 2D AIThe SynGAP1 missense variant E1282Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | -2.785 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 1.05 | Neutral | 0.004 | Benign | 0.003 | Benign | 2.70 | Benign | 0.31 | Tolerated | 0.0965 | 0.5651 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3845A>C | E1282A 2D AIThe SynGAP1 missense variant E1282A is not reported in ClinVar and is absent from gnomAD. Across the available in‑silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are present. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the computational evidence overwhelmingly supports a benign impact, and this conclusion does not contradict any ClinVar status, as none exists for E1282A. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | -1.980 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.118 | Likely Benign | 0.52 | Neutral | 0.026 | Benign | 0.018 | Benign | 2.94 | Benign | 0.38 | Tolerated | 0.3411 | 0.5358 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3846G>C | E1282D 2D AIThe SynGAP1 missense variant E1282D is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33447894-G-C). All available in silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) 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 computational evidence overwhelmingly supports a benign 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 Benign | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | Uncertain | 1 | 6-33447894-G-C | 1 | 6.44e-7 | -3.879 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.26 | Neutral | 0.112 | Benign | 0.036 | Benign | 2.70 | Benign | 0.39 | Tolerated | 3.77 | 5 | 0.1826 | 0.3464 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||
| c.3846G>T | E1282D 2D AIThe SynGAP1 missense variant E1282D is reported in gnomAD (ID 6‑33447894‑G‑T) but has no ClinVar entry. All in‑silico predictors reviewed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. No tool predicts pathogenicity, so the benign group includes every listed predictor, while the pathogenic group is empty. High‑accuracy assessments further support a benign effect: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign.” Foldetta results are unavailable. Overall, 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 | 0.754692 | Disordered | 0.817364 | Binding | 0.465 | 0.725 | 0.875 | 6-33447894-G-T | -3.879 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.104 | Likely Benign | -1.26 | Neutral | 0.112 | Benign | 0.036 | Benign | 2.70 | Benign | 0.39 | Tolerated | 3.77 | 5 | 0.1826 | 0.3464 | 3 | 2 | 0.0 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3847C>A | P1283T 2D AIThe SynGAP1 missense variant P1283T is catalogued in gnomAD (ID 6‑33447895‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Therefore, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | 6-33447895-C-A | -4.781 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.45 | Neutral | 0.451 | Benign | 0.193 | Benign | 2.76 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1269 | 0.3784 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3847C>G | P1283A 2D AIThe SynGAP1 missense variant P1283A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are unavailable, so they do not influence the overall assessment. Consequently, the variant is most likely benign based on the collective predictions, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | -3.656 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 1.42 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.79 | Benign | 1.00 | Tolerated | 0.2874 | 0.3370 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3847C>T | P1283S 2D AIThe SynGAP1 missense variant P1283S is catalogued in gnomAD (ID 6‑33447895‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Therefore, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | 6-33447895-C-T | -4.289 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.040 | Likely Benign | 0.06 | Neutral | 0.292 | Benign | 0.110 | Benign | 2.86 | Benign | 0.30 | Tolerated | 3.77 | 5 | 0.2837 | 0.3719 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.3848C>T | P1283L 2D AIThe SynGAP1 missense variant P1283L is listed in ClinVar (ID 536994.0) as Benign and is present in gnomAD (gnomAD ID 6‑33447896‑C‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts Benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, aligning with the ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.819686 | Binding | 0.484 | 0.732 | 0.875 | Benign | 1 | 6-33447896-C-T | 32 | 2.06e-5 | -3.740 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -1.04 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.76 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.1878 | 0.4716 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.3850C>G | L1284V 2D AIThe SynGAP1 missense variant L1284V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.824557 | Binding | 0.441 | 0.748 | 0.875 | -4.329 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.90 | Neutral | 0.008 | Benign | 0.006 | Benign | 2.92 | Benign | 1.00 | Tolerated | 0.1419 | 0.1883 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3853C>A | P1285T 2D AIThe SynGAP1 missense variant P1285T is catalogued in gnomAD (ID 6‑33447901‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, 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 | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447901-C-A | -4.230 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.35 | Neutral | 0.451 | Benign | 0.193 | Benign | 4.33 | Benign | 0.40 | Tolerated | 4.32 | 2 | 0.1496 | 0.3556 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3853C>G | P1285A 2D AIThe SynGAP1 missense variant P1285A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | -3.902 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.52 | Neutral | 0.264 | Benign | 0.070 | Benign | 4.27 | Benign | 0.71 | Tolerated | 0.2944 | 0.2974 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3853C>T | P1285S 2D AIThe SynGAP1 missense variant P1285S is reported in gnomAD (variant ID 6‑33447901‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign impact, and this is not in conflict with ClinVar, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447901-C-T | 1 | 6.44e-7 | -3.875 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -1.27 | Neutral | 0.802 | Possibly Damaging | 0.249 | Benign | 4.34 | Benign | 0.29 | Tolerated | 4.32 | 2 | 0.2912 | 0.3319 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3854C>A | P1285Q 2D  AIThe SynGAP1 missense variant P1285Q is reported in gnomAD (variant ID 6‑33447902‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447902-C-A | -4.073 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.67 | Neutral | 0.977 | Probably Damaging | 0.632 | Possibly Damaging | 4.22 | Benign | 0.13 | Tolerated | 4.32 | 2 | 0.1476 | 0.3025 | -1 | 0 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||||||
| c.3854C>G | P1285R 2D AIThe SynGAP1 missense variant P1285R is reported in gnomAD (variant ID 6‑33447902‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | 6-33447902-C-G | -3.417 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -2.10 | Neutral | 0.977 | Probably Damaging | 0.632 | Possibly Damaging | 4.22 | Benign | 0.14 | Tolerated | 4.32 | 2 | 0.1564 | 0.2194 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3854C>T | P1285L 2D AIThe SynGAP1 missense variant P1285L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification for P1285L, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.821643 | Binding | 0.557 | 0.759 | 0.750 | -3.663 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.06 | Neutral | 0.072 | Benign | 0.029 | Benign | 4.31 | Benign | 1.00 | Tolerated | 0.2159 | 0.4539 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3858A>C | E1286D 2D AIThe SynGAP1 missense variant E1286D is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta results are not available. Based on the unanimous benign predictions and lack of ClinVar evidence, the variant is most likely benign and does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2114 | 0.3141 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||||||
| c.3858A>T | E1286D 2D AIThe SynGAP1 missense variant E1286D is listed in ClinVar (ID 469159.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33447906‑A‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool in the set predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “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 computational evidence strongly supports a benign effect, 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 | 0.852992 | Disordered | 0.817022 | Binding | 0.544 | 0.765 | 0.750 | Conflicting | 4 | 6-33447906-A-T | 143 | 9.22e-5 | -4.010 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 1.02 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.96 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2114 | 0.3141 | 3 | 2 | 0.0 | -14.03 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3859C>G | P1287A 2D AIThe SynGAP1 missense variant P1287A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | -3.064 | Likely Benign | 0.065 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.51 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.91 | Benign | 0.57 | Tolerated | 0.2885 | 0.3222 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3859C>T | P1287S 2D AIThe SynGAP1 missense variant P1287S is catalogued in gnomAD (ID 6‑33447907‑C‑T) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently scores the variant as benign. No pathogenic predictions are reported. Grouping by agreement, the benign‑predicting tools comprise the entire set, while the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is assigned). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.813701 | Binding | 0.538 | 0.777 | 0.750 | 6-33447907-C-T | -3.258 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.055 | Likely Benign | 0.70 | Neutral | 0.004 | Benign | 0.004 | Benign | 2.96 | Benign | 0.96 | Tolerated | 3.77 | 5 | 0.2820 | 0.3566 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||
| c.385T>A | S129T 2D AIThe SynGAP1 missense variant S129T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -4.296 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.134 | Likely Benign | 0.12 | Neutral | 0.016 | Benign | 0.021 | Benign | 4.14 | Benign | 0.85 | Tolerated | 0.1251 | 0.5794 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.385T>C | S129P 2D AIThe SynGAP1 missense variant S129P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates 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 confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -2.469 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.220 | Likely Benign | -0.09 | Neutral | 0.454 | Possibly Damaging | 0.133 | Benign | 4.11 | Benign | 0.32 | Tolerated | 0.1998 | 0.4989 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.385T>G | S129A 2D AIThe SynGAP1 missense variant S129A is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors—including REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as benign. No tool predicts pathogenicity. 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 predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.713635 | Binding | 0.311 | 0.880 | 0.625 | -3.388 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.08 | Neutral | 0.007 | Benign | 0.007 | Benign | 4.21 | Benign | 0.15 | Tolerated | 0.5031 | 0.4619 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.3865A>C | K1289Q 2D AIThe SynGAP1 missense variant K1289Q is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the lack of a ClinVar entry, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -2.940 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.55 | Neutral | 0.004 | Benign | 0.004 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.4002 | 0.0590 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3866A>G | K1289R 2D AIThe SynGAP1 missense variant K1289R 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), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. 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) indicates a likely benign effect. Foldetta results are unavailable. Overall, the computational evidence strongly suggests 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 | 0.733139 | Disordered | 0.828700 | Binding | 0.548 | 0.787 | 0.625 | -2.127 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.090 | Likely Benign | -0.62 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.66 | Benign | 0.11 | Tolerated | 0.4046 | 0.0715 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3869G>A | R1290K 2D AIThe SynGAP1 missense variant R1290K is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.784345 | Disordered | 0.844138 | Binding | 0.567 | 0.795 | 0.625 | -3.749 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.037 | Likely Benign | 0.52 | Neutral | 0.004 | Benign | 0.006 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.3342 | 0.3113 | 3 | 2 | 0.6 | -28.01 | |||||||||||||||||||||||||||||||||||||||
| c.3871C>G | L1291V 2D AIThe SynGAP1 missense variant L1291V is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity, so the pathogenic prediction group is empty. High‑accuracy assessments corroborate this benign consensus: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this prediction aligns with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.863458 | Binding | 0.579 | 0.797 | 0.625 | -4.583 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.028 | Likely Benign | 0.28 | Neutral | 0.149 | Benign | 0.064 | Benign | 2.61 | Benign | 0.07 | Tolerated | 0.1435 | 0.2946 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3874C>A | L1292I 2D  AIThe SynGAP1 missense variant L1292I is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -5.480 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.050 | Likely Benign | 0.71 | Neutral | 0.002 | Benign | 0.006 | Benign | 3.23 | Benign | 1.00 | Tolerated | 0.1101 | 0.3323 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3874C>G | L1292V 2D AIThe SynGAP1 missense variant L1292V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar annotation (none present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.882643 | Binding | 0.586 | 0.800 | 0.625 | -4.943 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.14 | Neutral | 0.058 | Benign | 0.038 | Benign | 2.67 | Benign | 0.07 | Tolerated | 0.1769 | 0.2605 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.388C>A | Q130K 2D AIThe SynGAP1 missense variant Q130K is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around benign: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate a benign effect, 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) predict a pathogenic impact. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictors—AlphaMissense‑Optimized and the SGM‑Consensus—both support a benign classification, whereas the pathogenic predictions come from polyPhen‑2 alone. Based on the preponderance of evidence, the variant is most likely benign, 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 | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -4.656 | Likely Benign | 0.540 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -0.41 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.20 | Benign | 0.07 | Tolerated | 0.2017 | 0.4473 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.388C>G | Q130E 2D AIThe SynGAP1 missense variant Q130E is reported in gnomAD (ID 6‑33432685‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority of the same four tools) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple prediction algorithms indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | 6-33432685-C-G | 2 | 1.24e-6 | -4.283 | Likely Benign | 0.251 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.72 | Neutral | 0.924 | Possibly Damaging | 0.857 | Possibly Damaging | 4.19 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.1620 | 0.2587 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||
| c.3890G>A | R1297K 2D AIThe SynGAP1 missense variant R1297K is catalogued in gnomAD (ID 6‑33451764‑G‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated or benign. Grouping by consensus, all listed predictors fall into the benign category, with no tool reporting a pathogenic outcome. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign classification. Foldetta stability analysis is unavailable for this variant. Consequently, the aggregate evidence strongly supports a benign interpretation, and this assessment does not conflict with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | 6-33451764-G-A | 1 | 6.20e-7 | -3.780 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.074 | Likely Benign | 0.55 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.80 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4109 | 0.2801 | 2 | 3 | 0.6 | -28.01 | ||||||||||||||||||||||||||||||||||
| c.3890G>C | R1297T 2D AIThe SynGAP1 missense variant R1297T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools cluster into two groups: seven tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, while two tools (PROVEAN, FATHMM) predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.941 | Likely Benign | 0.287 | Likely Benign | Likely Benign | 0.151 | Likely Benign | -2.95 | Deleterious | 0.224 | Benign | 0.171 | Benign | 2.49 | Pathogenic | 0.08 | Tolerated | 0.1634 | 0.2972 | -1 | -1 | 3.8 | -55.08 | ||||||||||||||||||||||||||||||||||||||||
| c.3891G>C | R1297S 2D AIThe SynGAP1 missense variant R1297S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. 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, so they do not influence the assessment. Overall, the consensus of available predictions indicates that R1297S 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 | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.468 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -2.39 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.50 | Benign | 0.07 | Tolerated | 0.2863 | 0.2347 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3891G>T | R1297S 2D AIThe SynGAP1 missense variant R1297S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions strongly suggests that R1297S 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 | 0.859585 | Disordered | 0.895222 | Binding | 0.511 | 0.817 | 0.625 | -3.468 | Likely Benign | 0.401 | Ambiguous | Likely Benign | 0.139 | Likely Benign | -2.39 | Neutral | 0.224 | Benign | 0.096 | Benign | 2.50 | Benign | 0.07 | Tolerated | 0.2863 | 0.2347 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.3892C>A | Q1298K 2D AIThe SynGAP1 missense variant Q1298K is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is not contradicted by 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -3.415 | Likely Benign | 0.228 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -0.27 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.86 | Benign | 0.24 | Tolerated | 0.1360 | 0.2903 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.3892C>G | Q1298E 2D AIThe SynGAP1 missense variant Q1298E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is benign, and this conclusion does not contradict any ClinVar annotation (none present). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -3.530 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -1.14 | Neutral | 0.026 | Benign | 0.018 | Benign | 2.83 | Benign | 0.06 | Tolerated | 0.1235 | 0.1330 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.3893A>G | Q1298R 2D AIThe SynGAP1 missense variant Q1298R is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -2.643 | Likely Benign | 0.174 | Likely Benign | Likely Benign | 0.112 | Likely Benign | 1.38 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.15 | Benign | 1.00 | Tolerated | 0.1142 | 0.1628 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.3895C>A | L1299I 2D AIThe SynGAP1 missense variant L1299I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -5.264 | Likely Benign | 0.116 | Likely Benign | Likely Benign | 0.396 | Likely Benign | 0.71 | Neutral | 0.003 | Benign | 0.004 | Benign | 3.20 | Benign | 1.00 | Tolerated | 0.1014 | 0.3893 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.3895C>G | L1299V 2D AIThe SynGAP1 missense variant L1299V is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification—there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -4.502 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.385 | Likely Benign | -0.02 | Neutral | 0.124 | Benign | 0.025 | Benign | 2.89 | Benign | 0.09 | Tolerated | 0.1726 | 0.3544 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3895C>T | L1299F 2D  AIThe SynGAP1 missense variant L1299F is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.896323 | Binding | 0.398 | 0.832 | 0.750 | -5.618 | Likely Benign | 0.171 | Likely Benign | Likely Benign | 0.138 | Likely Benign | -1.80 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.69 | Benign | 0.42 | Tolerated | 0.0707 | 0.3342 | 2 | 0 | -1.0 | 34.02 | |||||||||||||||||||||||||||||||||||||||
| c.3898C>A | P1300T 2D AIThe SynGAP1 missense variant P1300T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates a pathogenic effect, while the SGM‑Consensus (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 also reports Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence supports a benign classification, 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | -4.522 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -0.64 | Neutral | 0.649 | Possibly Damaging | 0.266 | Benign | 2.87 | Benign | 0.21 | Tolerated | 0.1546 | 0.4729 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3898C>G | P1300A 2D AIThe SynGAP1 missense variant P1300A is reported in gnomAD (ID 6‑33451772‑C‑G) and has no ClinVar entry. Across the evaluated in‑silico tools, every predictor classifies the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the unanimous benign predictions and the absence of any pathogenic signal, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451772-C-G | 2 | 1.24e-6 | -3.802 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.065 | Likely Benign | 0.55 | Neutral | 0.008 | Benign | 0.006 | Benign | 3.23 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3342 | 0.3744 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3898C>T | P1300S 2D AIThe SynGAP1 missense variant P1300S is reported in gnomAD (variant ID 6‑33451772‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv flags it as pathogenic, creating a single discordant call. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that P1300S 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 | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451772-C-T | 1 | 6.20e-7 | -3.476 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.036 | Likely Benign | -0.29 | Neutral | 0.481 | Possibly Damaging | 0.157 | Benign | 2.89 | Benign | 0.27 | Tolerated | 3.77 | 5 | 0.3242 | 0.4139 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3899C>T | P1300L 2D AIThe SynGAP1 missense variant P1300L is reported in gnomAD (variant ID 6‑33451773‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts 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 consensus of the majority of tools, including the high‑accuracy methods, supports a benign interpretation. This prediction does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.885826 | Binding | 0.400 | 0.834 | 0.875 | 6-33451773-C-T | 1 | 6.20e-7 | -3.562 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -1.35 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 2.84 | Benign | 0.19 | Tolerated | 3.77 | 5 | 0.2348 | 0.5680 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3901C>A | P1301T 2D AIThe SynGAP1 missense variant P1301T is reported in gnomAD (ID 6‑33451775‑C‑A) and has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the consensus of all available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451775-C-A | 1 | 6.20e-7 | -4.945 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.34 | Neutral | 0.000 | Benign | 0.001 | Benign | 2.87 | Benign | 0.47 | Tolerated | 3.77 | 5 | 0.1255 | 0.3312 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||
| c.3901C>G | P1301A 2D AIThe SynGAP1 missense variant P1301A is catalogued in gnomAD (ID 6‑33451775‑C‑G) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated or benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta, a protein‑folding stability predictor, was not available for this residue. Overall, the consensus of all available predictions is benign, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451775-C-G | 1 | 6.20e-7 | -4.290 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.088 | Likely Benign | 0.66 | Neutral | 0.003 | Benign | 0.012 | Benign | 3.05 | Benign | 0.88 | Tolerated | 3.77 | 5 | 0.2850 | 0.3087 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3901C>T | P1301S 2D AIThe SynGAP1 missense variant P1301S is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly supports a benign effect, 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | -4.537 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.087 | Likely Benign | 1.84 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.29 | Benign | 0.95 | Tolerated | 0.2799 | 0.3436 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3902C>G | P1301R 2D AIThe SynGAP1 missense variant P1301R is listed in ClinVar with an uncertain significance (ClinVar ID 2092739.0) and is present in gnomAD (ID 6‑33451776‑C‑G). Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. In summary, all available predictions agree on 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | Uncertain | 1 | 6-33451776-C-G | 15 | 9.30e-6 | -4.753 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -1.13 | Neutral | 0.077 | Benign | 0.059 | Benign | 2.81 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.1352 | 0.1929 | 0 | -2 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||
| c.3902C>T | P1301L 2D AIThe SynGAP1 missense variant P1301L is reported in gnomAD (ID 6‑33451776‑C‑T) and has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Based on the unanimous benign predictions and lack of ClinVar pathogenic annotation, 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 | 0.728858 | Disordered | 0.885064 | Binding | 0.447 | 0.841 | 0.875 | 6-33451776-C-T | 3 | 1.86e-6 | -4.152 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.63 | Neutral | 0.017 | Benign | 0.028 | Benign | 2.83 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.1886 | 0.4655 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||
| c.3907G>A | G1303S 2D AIThe SynGAP1 missense variant G1303S is listed in ClinVar (ID 1736068.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only polyPhen‑2 HumDiv predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; a Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact, and this 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 | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | Uncertain | 1 | -2.271 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.155 | Likely Benign | -0.19 | Neutral | 0.649 | Possibly Damaging | 0.433 | Benign | 2.84 | Benign | 0.18 | Tolerated | 0.2605 | 0.4197 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||||||||||
| c.3908G>A | G1303D 2D AIThe SynGAP1 missense variant G1303D is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -3.825 | Likely Benign | 0.329 | Likely Benign | Likely Benign | 0.103 | Likely Benign | 2.64 | Neutral | 0.002 | Benign | 0.008 | Benign | 3.22 | Benign | 1.00 | Tolerated | 0.1784 | 0.1452 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||||||||||||
| c.3908G>C | G1303A 2D AIThe SynGAP1 missense variant G1303A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only polyPhen‑2 HumDiv indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.886612 | Binding | 0.429 | 0.854 | 0.875 | -2.637 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.29 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 2.83 | Benign | 0.11 | Tolerated | 0.3822 | 0.4092 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>A | P1304T 2D AIThe SynGAP1 missense variant P1304T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the collective evidence strongly supports a benign classification, and this conclusion does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.454 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.091 | Likely Benign | -0.42 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.86 | Benign | 0.14 | Tolerated | 0.1571 | 0.4914 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>G | P1304A 2D AIThe SynGAP1 missense variant P1304A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | -4.072 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.35 | Neutral | 0.001 | Benign | 0.002 | Benign | 3.09 | Benign | 1.00 | Tolerated | 0.2923 | 0.4117 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3910C>T | P1304S 2D AIThe SynGAP1 missense variant P1304S is reported in gnomAD (ID 6‑33451784‑C‑T) but has no ClinVar entry. Functional prediction tools uniformly classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “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 (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | 6-33451784-C-T | 1 | 6.20e-7 | -4.103 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.36 | Neutral | 0.059 | Benign | 0.041 | Benign | 3.03 | Benign | 0.58 | Tolerated | 3.77 | 5 | 0.2900 | 0.4442 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3911C>T | P1304L 2D AIThe SynGAP1 missense variant P1304L is reported in gnomAD (ID 6‑33451785‑C‑T) and has no ClinVar entry. All evaluated in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a likely benign outcome, while AlphaMissense‑Optimized independently scores it benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Based on the unanimous benign predictions and the absence of any ClinVar pathogenic classification, the variant is most likely benign and does not contradict existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.886417 | Binding | 0.475 | 0.866 | 0.875 | 6-33451785-C-T | 1 | 6.20e-7 | -4.080 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -1.33 | Neutral | 0.126 | Benign | 0.066 | Benign | 2.83 | Benign | 0.06 | Tolerated | 0.2200 | 0.5478 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||||||
| c.3913A>G | T1305A 2D  AIThe SynGAP1 missense variant T1305A is listed in ClinVar (ID 411587.0) with an “Uncertain” clinical significance and is present in the gnomAD database (variant ID 6‑33451787‑A‑G). All evaluated in‑silico predictors classify the change as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic or likely pathogenic outcome. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | Conflicting | 4 | 6-33451787-A-G | 30 | 1.86e-5 | -2.692 | Likely Benign | 0.055 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 1.74 | Neutral | 0.000 | Benign | 0.001 | Benign | 3.24 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.4533 | 0.4746 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||||
| c.3913A>T | T1305S 2D AIThe SynGAP1 missense variant T1305S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -2.813 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.20 | Neutral | 0.003 | Benign | 0.026 | Benign | 2.83 | Benign | 0.08 | Tolerated | 0.3683 | 0.4988 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3919C>A | P1307T 2D AIThe SynGAP1 missense variant P1307T is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly suggests that P1307T is most likely benign, and this conclusion is consistent with the lack of ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -4.262 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.072 | Likely Benign | 0.20 | Neutral | 0.386 | Benign | 0.266 | Benign | 3.07 | Benign | 0.60 | Tolerated | 0.1732 | 0.5436 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3919C>G | P1307A 2D AIThe SynGAP1 missense variant P1307A is catalogued in gnomAD (ID 6‑33451793‑C‑G) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated or benign. No tool in the dataset predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as likely benign. Foldetta, a protein‑folding stability predictor, was not available for this variant. Overall, the consensus of all available predictions is benign, and this is consistent with the absence of a ClinVar pathogenic classification. Based on the consensus of all predictions, the variant is most likely benign, and this does not contradict ClinVar status, which has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | 6-33451793-C-G | 1 | 6.20e-7 | -4.042 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.49 | Neutral | 0.003 | Benign | 0.006 | Benign | 3.11 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3747 | 0.4451 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3919C>T | P1307S 2D AIThe SynGAP1 missense variant P1307S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -3.700 | Likely Benign | 0.093 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.45 | Neutral | 0.239 | Benign | 0.157 | Benign | 3.09 | Benign | 0.48 | Tolerated | 0.3652 | 0.4846 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3920C>G | P1307R 2D AIThe SynGAP1 missense variant P1307R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy methods further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that P1307R is most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.798249 | Disordered | 0.913511 | Binding | 0.491 | 0.901 | 0.875 | -4.022 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.225 | Likely Benign | -1.17 | Neutral | 0.887 | Possibly Damaging | 0.664 | Possibly Damaging | 2.82 | Benign | 0.06 | Tolerated | 0.1552 | 0.2763 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3925G>C | V1309L 2D AIThe SynGAP1 missense variant V1309L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this trend: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.543 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 1.41 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.0944 | 0.4212 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3925G>T | V1309L 2D AIThe SynGAP1 missense variant V1309L is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the computational evidence strongly supports a benign impact, 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 | 0.712013 | Disordered | 0.948596 | Binding | 0.402 | 0.907 | 0.750 | -2.543 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.108 | Likely Benign | 1.41 | Neutral | 0.000 | Benign | 0.002 | Benign | 2.99 | Benign | 1.00 | Tolerated | 0.0944 | 0.4212 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3928A>G | T1310A 2D AIThe SynGAP1 missense variant T1310A is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -2.883 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.084 | Likely Benign | -0.21 | Neutral | 0.041 | Benign | 0.039 | Benign | 2.83 | Benign | 0.13 | Tolerated | 0.3238 | 0.3177 | 1 | 0 | 2.5 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.3928A>T | T1310S 2D AIThe SynGAP1 missense variant T1310S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, 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 Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | -2.809 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.23 | Neutral | 0.089 | Benign | 0.120 | Benign | 2.80 | Benign | 0.17 | Tolerated | 0.2629 | 0.3418 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3929C>T | T1310M 2D  AIThe SynGAP1 missense variant T1310M is listed in ClinVar (ID 2160201.0) as Benign and is present in gnomAD (gnomAD ID 6‑33451803‑C‑T). All evaluated in‑silico predictors report a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign classification, which aligns with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.959076 | Binding | 0.398 | 0.904 | 0.750 | Benign | 1 | 6-33451803-C-T | 17 | 1.05e-5 | -4.822 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.069 | Likely Benign | 2.19 | Neutral | 0.021 | Benign | 0.005 | Benign | 2.98 | Benign | 0.93 | Tolerated | 3.77 | 5 | 0.1144 | 0.5397 | -1 | -1 | 2.6 | 30.09 | ||||||||||||||||||||||||||||||||
| c.3931C>A | L1311M 2D AIThe SynGAP1 missense variant L1311M is reported in gnomAD (ID 6‑33451805‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all 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) predict a pathogenic impact. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence supports a benign classification for L1311M, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.968153 | Binding | 0.393 | 0.907 | 0.750 | 6-33451805-C-A | 3 | 1.86e-6 | -4.817 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.060 | Likely Benign | 0.18 | Neutral | 0.936 | Possibly Damaging | 0.632 | Possibly Damaging | 2.73 | Benign | 0.23 | Tolerated | 3.77 | 5 | 0.1068 | 0.4279 | 2 | 4 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||
| c.3931C>G | L1311V 2D AIThe SynGAP1 missense variant L1311V is catalogued in gnomAD (ID 6‑33451805‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports 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 | 0.816150 | Disordered | 0.968153 | Binding | 0.393 | 0.907 | 0.750 | 6-33451805-C-G | 1 | 6.20e-7 | -3.645 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.05 | Neutral | 0.362 | Benign | 0.193 | Benign | 2.89 | Benign | 0.32 | Tolerated | 3.77 | 5 | 0.1666 | 0.3518 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3932T>A | L1311Q 2D AIThe SynGAP1 missense variant L1311Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts 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; the Foldetta protein‑folding stability analysis is unavailable. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.968153 | Binding | 0.393 | 0.907 | 0.750 | -4.009 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.03 | Neutral | 0.579 | Possibly Damaging | 0.413 | Benign | 2.74 | Benign | 0.12 | Tolerated | 0.1476 | 0.1677 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.3932T>C | L1311P 2D AIThe SynGAP1 missense variant L1311P is listed in ClinVar (ID 833866.0) as Benign and is present in gnomAD (variant ID 6‑33451806‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, and AlphaMissense‑Optimized also reports Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar benign annotation and does not contradict the database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.968153 | Binding | 0.393 | 0.907 | 0.750 | Likely Benign | 1 | 6-33451806-T-C | 1 | 6.21e-7 | -1.831 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -0.52 | Neutral | 0.579 | Possibly Damaging | 0.335 | Benign | 2.72 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.3181 | 0.1794 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||
| c.3932T>G | L1311R 2D AIThe SynGAP1 missense variant L1311R is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors indicates a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the change as tolerated or benign. Only polyPhen‑2 HumDiv classifies it as pathogenic, but this is the sole discordant call. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy tools 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 evidence overwhelmingly points to a benign impact, 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 | 0.816150 | Disordered | 0.968153 | Binding | 0.393 | 0.907 | 0.750 | -3.794 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.083 | Likely Benign | -0.36 | Neutral | 0.579 | Possibly Damaging | 0.267 | Benign | 2.74 | Benign | 0.12 | Tolerated | 0.1611 | 0.1719 | -3 | -2 | -8.3 | 43.03 | |||||||||||||||||||||||||||||||||||||||
| c.3937C>A | P1313T 2D AIThe SynGAP1 missense variant P1313T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.666 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.149 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.26 | Benign | 0.14 | Tolerated | 0.1889 | 0.7040 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.3937C>G | P1313A 2D AIThe SynGAP1 missense variant P1313A is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this benign classification: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly suggests that P1313A is most likely benign, 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 | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -3.855 | Likely Benign | 0.054 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.37 | Neutral | 0.021 | Benign | 0.028 | Benign | 4.27 | Benign | 0.25 | Tolerated | 0.3529 | 0.5842 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||||||||||||
| c.3937C>T | P1313S 2D AIThe SynGAP1 missense variant P1313S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as benign. No tool in the dataset predicts pathogenicity. The high‑accuracy consensus methods likewise support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign.” Foldetta results are not available, so they do not influence the assessment. Overall, the collective evidence strongly suggests that the variant is most likely benign, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.279 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.067 | Likely Benign | -0.03 | Neutral | 0.047 | Benign | 0.066 | Benign | 4.33 | Benign | 0.13 | Tolerated | 0.3520 | 0.6153 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3938C>A | P1313Q 2D AIThe SynGAP1 missense variant P1313Q is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, is not available for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.533 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.063 | Likely Benign | 0.99 | Neutral | 0.324 | Benign | 0.287 | Benign | 4.31 | Benign | 0.15 | Tolerated | 0.1748 | 0.5651 | 0 | -1 | -1.9 | 31.01 | |||||||||||||||||||||||||||||||||||||||
| c.3938C>G | P1313R 2D AIThe SynGAP1 missense variant P1313R is not reported in ClinVar and has no entry in gnomAD. Prediction tools that assess pathogenicity are unanimous: all listed algorithms (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a benign effect, while none predict pathogenicity. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and the protein‑folding stability tool Foldetta provides no result, so it does not influence the assessment. Based on the collective predictions, 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 | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.634 | Likely Benign | 0.161 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -0.52 | Neutral | 0.324 | Benign | 0.172 | Benign | 4.25 | Benign | 0.22 | Tolerated | 0.1659 | 0.4742 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3938C>T | P1313L 2D AIThe SynGAP1 missense variant P1313L is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population evidence. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.862302 | Disordered | 0.970301 | Binding | 0.452 | 0.902 | 0.750 | -4.588 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.082 | Likely Benign | 1.90 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.30 | Benign | 1.00 | Tolerated | 0.2489 | 0.6948 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3940C>A | P1314T 2D AIThe SynGAP1 missense variant P1314T is present in gnomAD (ID 6‑33451814‑C‑A) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect. Benign predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status remains unavailable. Overall, the computational evidence overwhelmingly supports a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this is consistent with the lack of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | 6-33451814-C-A | -4.083 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.26 | Neutral | 0.061 | Benign | 0.045 | Benign | 4.32 | Benign | 0.97 | Tolerated | 3.77 | 5 | 0.1791 | 0.5626 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3940C>G | P1314A 2D AIThe SynGAP1 missense variant P1314A is catalogued in gnomAD (ID 6‑33451814‑C‑G) but has no ClinVar entry. Across the spectrum of in silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—returns a benign or likely benign verdict. No pathogenic predictions appear in the dataset, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized scores benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Taken together, the evidence overwhelmingly supports a benign classification, and this conclusion does not conflict with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | 6-33451814-C-G | 1 | 6.22e-7 | -3.540 | Likely Benign | 0.061 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.23 | Benign | 0.93 | Tolerated | 3.77 | 5 | 0.3502 | 0.4441 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3940C>T | P1314S 2D AIThe SynGAP1 missense variant P1314S has no ClinVar entry and is not reported in gnomAD. All evaluated in‑silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the computational evidence strongly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | -3.838 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.046 | Likely Benign | 0.11 | Neutral | 0.005 | Benign | 0.003 | Benign | 4.22 | Benign | 0.72 | Tolerated | 0.3522 | 0.4751 | 1 | -1 | 0.8 | -10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3941C>G | P1314R 2D AIThe SynGAP1 missense variant P1314R is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 results are not available, so they do not influence the overall assessment. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.882776 | Disordered | 0.971592 | Binding | 0.467 | 0.903 | 0.750 | -4.234 | Likely Benign | 0.168 | Likely Benign | Likely Benign | 0.036 | Likely Benign | 0.01 | Neutral | 0.618 | Possibly Damaging | 0.206 | Benign | 4.25 | Benign | 0.09 | Tolerated | 0.1634 | 0.3405 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||||||||||||
| c.3943T>A | W1315R 2D  AIThe SynGAP1 missense variant W1315R is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only AlphaMissense‑Default predicts a pathogenic outcome, representing the sole discordant signal. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from multiple prediction algorithms and high‑accuracy tools points to a benign effect, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.205 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.37 | Benign | 0.91 | Tolerated | 3.77 | 5 | 0.4317 | 0.0384 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||||||||||
| c.3943T>C | W1315R 2D AIThe SynGAP1 missense variant W1315R is listed in ClinVar (ID 1029092.0) with an “Uncertain” clinical significance and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as benign; Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | Uncertain | 1 | 0.205 | Likely Benign | 0.660 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.37 | Benign | 0.91 | Tolerated | 3.77 | 5 | 0.4317 | 0.0384 | 2 | -3 | -3.6 | -30.03 | |||||||||||||||||||||||||||||||||||
| c.3943T>G | W1315G 2D  AIThe SynGAP1 missense variant W1315G is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions strongly supports a benign classification, and this conclusion is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.687 | Likely Benign | 0.193 | Likely Benign | Likely Benign | 0.113 | Likely Benign | -1.36 | Neutral | 0.208 | Benign | 0.077 | Benign | 4.21 | Benign | 0.12 | Tolerated | 0.4126 | 0.1745 | -7 | -2 | 0.5 | -129.16 | |||||||||||||||||||||||||||||||||||||||
| c.3944G>C | W1315S 2D  AIThe SynGAP1 missense variant W1315S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.896 | Likely Benign | 0.279 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.79 | Neutral | 0.115 | Benign | 0.057 | Benign | 4.26 | Benign | 0.13 | Tolerated | 0.3974 | 0.1211 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||||||||||||
| c.3944G>T | W1315L 2D  AIThe SynGAP1 missense variant W1315L is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.973142 | Binding | 0.403 | 0.889 | 0.750 | 0.369 | Likely Benign | 0.304 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.65 | Neutral | 0.115 | Benign | 0.057 | Benign | 4.29 | Benign | 0.16 | Tolerated | 0.2256 | 0.3338 | -2 | -2 | 4.7 | -73.05 | |||||||||||||||||||||||||||||||||||||||
| c.3952C>G | L1318V 2D AIThe SynGAP1 missense variant L1318V is catalogued in gnomAD (ID 6‑33451826‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the computational evidence overwhelmingly supports a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar record, which contains no pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.968271 | Binding | 0.399 | 0.865 | 0.750 | 6-33451826-C-G | 1 | 6.31e-7 | -3.938 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.58 | Neutral | 0.113 | Benign | 0.028 | Benign | 4.08 | Benign | 0.75 | Tolerated | 3.77 | 5 | 0.1861 | 0.3027 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3955G>T | A1319S 2D AIThe SynGAP1 missense variant A1319S is catalogued in gnomAD (ID 6‑33451829‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly classify it as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign effects. No tool predicts pathogenicity. Grouping by consensus, all listed predictors fall into the benign category, with no pathogenic predictions to counterbalance. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized indicates benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | 6-33451829-G-T | -4.557 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.094 | Likely Benign | 0.79 | Neutral | 0.174 | Benign | 0.112 | Benign | 4.17 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2957 | 0.5676 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3956C>G | A1319G 2D AIThe SynGAP1 missense variant A1319G is listed in ClinVar (ID 1690510.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33451830‑C‑G). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of 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 results are unavailable. Overall, the majority of evidence points to a benign effect, and this is consistent with the ClinVar “Uncertain” status rather than contradicting it. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.842060 | Disordered | 0.960481 | Binding | 0.454 | 0.851 | 0.750 | Uncertain | 2 | 6-33451830-C-G | -3.927 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.128 | Likely Benign | -0.74 | Neutral | 0.819 | Possibly Damaging | 0.581 | Possibly Damaging | 4.07 | Benign | 0.06 | Tolerated | 3.77 | 5 | 0.2423 | 0.4541 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||
| c.3961C>A | P1321T 2D AIThe SynGAP1 missense variant P1321T is catalogued in gnomAD (ID 6‑33451835‑C‑A) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this conclusion is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451835-C-A | -4.946 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 1.07 | Neutral | 0.115 | Benign | 0.012 | Benign | 4.25 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2016 | 0.5901 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3961C>G | P1321A 2D AIThe SynGAP1 missense variant P1321A is reported in gnomAD (ID 6‑33451835‑C‑G) and has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective 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 | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451835-C-G | -4.411 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.33 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.29 | Benign | 0.42 | Tolerated | 3.77 | 5 | 0.3615 | 0.4716 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||
| c.3961C>T | P1321S 2D AIThe SynGAP1 missense variant P1321S is listed in ClinVar (ID 1806027.0) with an “Uncertain” clinical significance and is present in the gnomAD database (gnomAD ID 6‑33451835‑C‑T). All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic prediction. High‑accuracy assessments corroborate this benign trend: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 computational evidence strongly supports a benign effect, which is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | Uncertain | 2 | 6-33451835-C-T | 10 | 6.46e-6 | -4.897 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.049 | Likely Benign | 0.68 | Neutral | 0.028 | Benign | 0.004 | Benign | 4.27 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3610 | 0.5190 | 1 | -1 | 0.8 | -10.04 | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||||||||||||||||
| c.3962C>A | P1321Q 2D AIThe SynGAP1 missense variant P1321Q is listed in ClinVar (ID 833687.0) as benign and is present in gnomAD (variant ID 6‑33451836‑C‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized also reports 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‑confidence SGM consensus and AlphaMissense‑Optimized—supports a benign impact. This conclusion aligns with the ClinVar benign status, with no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | Benign | 1 | 6-33451836-C-A | 1 | 6.58e-7 | -5.594 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.74 | Neutral | 0.659 | Possibly Damaging | 0.034 | Benign | 4.24 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1839 | 0.4884 | 0 | -1 | -1.9 | 31.01 | ||||||||||||||||||||||||||||||||
| c.3962C>G | P1321R 2D AIThe SynGAP1 missense variant P1321R is reported in gnomAD (ID 6‑33451836‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool examined—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classifies the substitution as benign. No pathogenic predictions are present. Grouping the results, the benign consensus is unanimous; the pathogenic group is empty. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign status. Foldetta stability analysis is not available for this variant. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar classification (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | 6-33451836-C-G | 1 | 6.58e-7 | -5.310 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.034 | Likely Benign | -1.10 | Neutral | 0.389 | Benign | 0.024 | Benign | 4.25 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1722 | 0.3635 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||
| c.3962C>T | P1321L 2D AIThe SynGAP1 missense variant P1321L is not reported in ClinVar and is absent from gnomAD, indicating no documented allele frequency data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. Foldetta results are not available, so they do not influence the assessment. Overall, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.827927 | Disordered | 0.933505 | Binding | 0.463 | 0.828 | 0.875 | -4.892 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -0.81 | Neutral | 0.115 | Benign | 0.009 | Benign | 4.28 | Benign | 0.08 | Tolerated | 0.2626 | 0.6222 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.3964G>A | A1322T 2D AIThe SynGAP1 missense variant A1322T is catalogued in gnomAD (ID 6‑33451838‑G‑A) but has no ClinVar entry. All available in silico predictors classify it as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool reports a pathogenic outcome. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect. Foldetta, a protein‑folding stability method, has no reported result for this variant. Overall, the evidence strongly supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451838-G-A | -4.940 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.079 | Likely Benign | 0.51 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.27 | Tolerated | 3.77 | 5 | 0.1972 | 0.7582 | 0 | 1 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||
| c.3964G>C | A1322P 2D AIThe SynGAP1 missense variant A1322P is reported in ClinVar (ID 1169945.0) as benign and is present in gnomAD (variant ID 6‑33451838‑G‑C). Across the available in‑silico predictors, all tools uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign predictions. No tool in the dataset indicates a pathogenic effect. High‑accuracy assessments corroborate this consensus: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. The Foldetta protein‑folding stability analysis is not available for this variant. Overall, the computational evidence strongly supports a benign classification, which is consistent with the ClinVar status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | Benign | 1 | 6-33451838-G-C | -1.153 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.090 | Likely Benign | 0.03 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.15 | Benign | 0.23 | Tolerated | 3.77 | 5 | 0.2255 | 0.6094 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||||||
| c.3964G>T | A1322S 2D AIThe SynGAP1 missense variant A1322S is catalogued in gnomAD (ID 6‑33451838‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the evidence strongly supports a benign classification, 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 | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451838-G-T | -4.570 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.086 | Likely Benign | 1.38 | Neutral | 0.003 | Benign | 0.001 | Benign | 4.48 | Benign | 0.57 | Tolerated | 3.77 | 5 | 0.2954 | 0.6084 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||
| c.3965C>A | A1322D 2D AIThe SynGAP1 missense variant A1322D is catalogued in gnomAD (ID 6‑33451839‑C‑A) but has no ClinVar entry. Across the spectrum of in‑silico predictors, every tool listed—REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently classifies the substitution as benign. No pathogenic predictions are reported. Grouping by consensus, all available tools fall into the benign category, with no tools indicating pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no result for this variant, so its status is unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-A | -5.744 | Likely Benign | 0.284 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.70 | Neutral | 0.013 | Benign | 0.004 | Benign | 4.17 | Benign | 0.45 | Tolerated | 3.77 | 5 | 0.2246 | 0.3134 | -2 | 0 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||||||||
| c.3965C>G | A1322G 2D AIThe SynGAP1 missense variant A1322G is catalogued in gnomAD (ID 6‑33451839‑C‑G) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized indicates a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign status. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this prediction 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 | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-G | -4.159 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.053 | Likely Benign | 0.42 | Neutral | 0.005 | Benign | 0.002 | Benign | 4.16 | Benign | 0.62 | Tolerated | 3.77 | 5 | 0.2160 | 0.4741 | 0 | 1 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||||||||
| c.3965C>T | A1322V 2D AIThe SynGAP1 missense variant A1322V is catalogued in gnomAD (ID 6‑33451839‑C‑T) but has no ClinVar entry. Across a broad panel of in silico predictors, every tool reports a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool in the set predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized returns a benign prediction, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta results are not available for this variant. Taken together, the computational evidence overwhelmingly supports a benign effect, and this conclusion does not conflict with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.887230 | Disordered | 0.921040 | Binding | 0.466 | 0.825 | 0.875 | 6-33451839-C-T | -5.376 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 4.17 | Benign | 0.15 | Tolerated | 3.77 | 5 | 0.1507 | 0.6747 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||
| c.3979C>A | P1327T 2D AIThe SynGAP1 missense variant P1327T is reported in gnomAD (ID 6‑33451853‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign; Foldetta results are not available. Taken together, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451853-C-A | -5.263 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 0.144 | Likely Benign | 1.20 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.51 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1386 | 0.4779 | -1 | 0 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||||||||
| c.3979C>G | P1327A 2D AIThe SynGAP1 missense variant P1327A is reported in gnomAD (ID 6‑33451853‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) predict the variant to be pathogenic. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a pathogenic ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451853-C-G | 2 | 1.28e-6 | -4.661 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.37 | Neutral | 0.980 | Probably Damaging | 0.811 | Possibly Damaging | 4.24 | Benign | 0.42 | Tolerated | 3.77 | 5 | 0.3152 | 0.3645 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||
| c.3979C>T | P1327S 2D AIThe SynGAP1 missense variant P1327S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33451853‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic outcome. 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 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 | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451853-C-T | -4.744 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.092 | Likely Benign | 0.28 | Neutral | 0.980 | Probably Damaging | 0.857 | Possibly Damaging | 4.25 | Benign | 0.71 | Tolerated | 3.77 | 5 | 0.3098 | 0.4025 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.3980C>G | P1327R 2D AIThe SynGAP1 missense variant P1327R is reported in gnomAD (variant ID 6‑33451854‑C‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict the variant to be pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a likely benign outcome. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence, the variant is 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 | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | 6-33451854-C-G | -4.724 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.137 | Likely Benign | -0.95 | Neutral | 0.994 | Probably Damaging | 0.937 | Probably Damaging | 4.12 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.1442 | 0.2798 | -2 | 0 | -2.9 | 59.07 | ||||||||||||||||||||||||||||||||||||
| c.3980C>T | P1327L 2D AIThe SynGAP1 missense variant P1327L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33451854‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy AlphaMissense‑Optimized score is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates a benign outcome. Foldetta results are not available for this variant. Overall, the majority of computational evidence supports a benign classification, 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 | 0.896620 | Disordered | 0.900145 | Binding | 0.369 | 0.777 | 0.875 | Uncertain | 1 | 6-33451854-C-T | 2 | 1.28e-6 | -5.264 | Likely Benign | 0.242 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.24 | Neutral | 0.994 | Probably Damaging | 0.908 | Possibly Damaging | 4.12 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.2123 | 0.5538 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||||
| c.3988C>G | Q1330E 2D AIThe SynGAP1 missense variant Q1330E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only polyPhen‑2 HumDiv indicates 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 confirm this: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus also reports likely benign; Foldetta results are unavailable. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.428 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -1.12 | Neutral | 0.613 | Possibly Damaging | 0.240 | Benign | 3.98 | Benign | 0.06 | Tolerated | 0.1346 | 0.2409 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.4018A>T | T1340S 2D AIThe SynGAP1 missense variant T1340S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | -2.698 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.87 | Benign | 1.00 | Tolerated | 0.3436 | 0.4521 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4019C>G | T1340S 2D AIThe SynGAP1 missense variant T1340S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | -2.698 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.083 | Likely Benign | 0.62 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.87 | Benign | 1.00 | Tolerated | 0.3436 | 0.4521 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4021G>T | A1341S 2D AIThe SynGAP1 missense variant A1341S is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33451895-G-T). All available in silico predictors agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is benign; Foldetta results are not available. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.980111 | Binding | 0.383 | 0.696 | 1.000 | Uncertain | 1 | 6-33451895-G-T | -2.867 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.099 | Likely Benign | 0.80 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.40 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2784 | 0.5884 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||
| c.4024G>A | D1342N 2D  AIThe SynGAP1 missense variant D1342N is catalogued in gnomAD (ID 6‑33451898‑G‑A) but has no ClinVar submission. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated or benign. Grouping by consensus, all listed predictors fall into the benign category, with no tool reporting pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta stability analysis is unavailable for this variant. Consequently, the aggregate evidence strongly supports a benign classification, and this assessment does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | 6-33451898-G-A | -3.459 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.058 | Likely Benign | 0.29 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.07 | Benign | 0.93 | Tolerated | 4.32 | 4 | 0.1868 | 0.6022 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||||||||
| c.4025A>G | D1342G 2D  AIThe SynGAP1 missense variant D1342G is reported in gnomAD (variant ID 6‑33451899‑A‑G) but has no ClinVar entry. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | 6-33451899-A-G | 1 | 7.29e-7 | -3.227 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 0.021 | Likely Benign | -0.89 | Neutral | 0.225 | Benign | 0.045 | Benign | 4.05 | Benign | 0.09 | Tolerated | 4.32 | 4 | 0.3633 | 0.5601 | -1 | 1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||||||
| c.415A>C | S139R 2D AIThe SynGAP1 missense variant S139R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that agree on a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts benign. Foldetta results are unavailable. Overall, the majority of conventional predictors and the SGM Consensus favor a benign interpretation, whereas AlphaMissense‑Optimized suggests pathogenicity. No ClinVar annotation exists to contradict these predictions. Thus, based on the available computational evidence, the variant is most likely benign, though the AlphaMissense‑Optimized prediction introduces some uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -7.547 | In-Between | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.112 | Likely Benign | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 0.1004 | 0.2971 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.415A>G | S139G 2D AIThe SynGAP1 missense variant S139G is not reported in ClinVar and is absent from gnomAD, indicating no documented clinical or population data. Functional prediction tools uniformly classify the variant as benign: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. No tool predicts pathogenicity. The high‑accuracy consensus, SGM‑Consensus, also reports the variant as Likely Benign, and AlphaMissense‑Optimized confirms a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | 1.647 | Likely Benign | 0.159 | Likely Benign | Likely Benign | 0.116 | Likely Benign | 1.29 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.29 | Benign | 1.00 | Tolerated | 0.2712 | 0.3414 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.415A>T | S139C 2D AIThe SynGAP1 missense variant S139C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv and AlphaMissense‑Default predict 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 interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority 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 preponderance of evidence indicates that the S139C variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -6.964 | Likely Benign | 0.689 | Likely Pathogenic | Likely Benign | 0.087 | Likely Benign | -2.43 | Neutral | 0.876 | Possibly Damaging | 0.319 | Benign | 4.07 | Benign | 0.06 | Tolerated | 0.1273 | 0.4546 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.416G>A | S139N 2D AIThe SynGAP1 missense variant S139N is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33432713‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. 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 “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | Uncertain | 1 | 6-33432713-G-A | 3 | 2.22e-6 | -4.584 | Likely Benign | 0.688 | Likely Pathogenic | Likely Benign | 0.109 | Likely Benign | -0.75 | Neutral | 0.149 | Benign | 0.047 | Benign | 4.14 | Benign | 0.24 | Tolerated | 3.61 | 5 | 0.1526 | 0.3614 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||
| c.416G>C | S139T 2D AIThe SynGAP1 missense variant S139T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The high‑accuracy consensus (SGM‑Consensus) also indicates a likely benign classification, and AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the majority of computational evidence supports 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 | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -4.518 | Likely Benign | 0.463 | Ambiguous | Likely Benign | 0.122 | Likely Benign | -1.70 | Neutral | 0.034 | Benign | 0.023 | Benign | 4.13 | Benign | 0.25 | Tolerated | 0.1655 | 0.4416 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.417C>A | S139R 2D AIThe SynGAP1 missense variant S139R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence—including the consensus of high‑accuracy tools—suggests a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -7.547 | In-Between | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 0.1004 | 0.2971 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.417C>G | S139R 2D AIThe SynGAP1 missense variant S139R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.553315 | Disordered | 0.600637 | Binding | 0.353 | 0.900 | 0.250 | -7.547 | In-Between | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.110 | Likely Benign | -2.07 | Neutral | 0.380 | Benign | 0.136 | Benign | 4.16 | Benign | 0.12 | Tolerated | 0.1004 | 0.2971 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.418T>C | S140P 2D AIThe SynGAP1 missense variant S140P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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. High‑accuracy tools specifically show AlphaMissense‑Optimized as pathogenic, while SGM Consensus and Foldetta are unavailable. Overall, the majority of evidence points to a pathogenic impact for S140P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -4.089 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | -2.59 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 3.52 | Benign | 0.08 | Tolerated | 0.1726 | 0.5117 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.421A>C | I141L 2D AIThe SynGAP1 missense variant I141L 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), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) is not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.465241 | Structured | 0.577021 | Binding | 0.367 | 0.877 | 0.500 | -6.563 | Likely Benign | 0.787 | Likely Pathogenic | Ambiguous | 0.156 | Likely Benign | -1.00 | Neutral | 0.016 | Benign | 0.013 | Benign | 3.84 | Benign | 0.10 | Tolerated | 0.0742 | 0.3180 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||||||||||||
| c.442C>A | P148T 2D AIThe SynGAP1 missense variant P148T 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar entry to contradict this conclusion, so the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | -4.762 | Likely Benign | 0.781 | Likely Pathogenic | Likely Benign | 0.108 | Likely Benign | -1.39 | Neutral | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 4.03 | Benign | 0.15 | Tolerated | 0.1698 | 0.4850 | 0 | -1 | 0.9 | 3.99 | |||||||||||||||||||||||||||||||||||||||
| c.442C>T | P148S 2D AIThe SynGAP1 missense variant P148S is not reported in ClinVar (ClinVar status: not listed) and is present in gnomAD (ID 6‑33432739‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.500109 | Binding | 0.372 | 0.837 | 0.625 | 6-33432739-C-T | 1 | 6.33e-7 | -3.258 | Likely Benign | 0.874 | Likely Pathogenic | Ambiguous | 0.102 | Likely Benign | -1.81 | Neutral | 1.000 | Probably Damaging | 0.994 | Probably Damaging | 4.05 | Benign | 0.39 | Tolerated | 3.61 | 5 | 0.3143 | 0.4597 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||
| c.453C>A | D151E 2D  AIThe SynGAP1 D151E variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain,” SGM‑Consensus as “Likely Benign,” and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | Uncertain | 1 | -5.662 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -2.02 | Neutral | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 3.99 | Benign | 0.11 | Tolerated | 3.61 | 5 | 0.1494 | 0.7919 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.453C>G | D151E 2D AIThe SynGAP1 missense variant D151E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a Likely Benign classification, and AlphaMissense‑Optimized remains uncertain. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for D151E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.529623 | Disordered | 0.503277 | Binding | 0.342 | 0.841 | 0.625 | -5.662 | Likely Benign | 0.886 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -2.02 | Neutral | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 3.99 | Benign | 0.11 | Tolerated | 3.61 | 5 | 0.1494 | 0.7919 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.457A>T | T153S 2D AIThe SynGAP1 missense variant T153S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, 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 Benign | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -1.890 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.50 | Neutral | 0.235 | Benign | 0.039 | Benign | 4.19 | Benign | 0.14 | Tolerated | 0.3756 | 0.2886 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.458C>A | T153N 2D  AIThe SynGAP1 missense variant T153N is listed in ClinVar (ID 984906.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while 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) predict pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence supports a benign classification, and this is consistent with the ClinVar “Uncertain” designation rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | Conflicting | 3 | -0.739 | Likely Benign | 0.226 | Likely Benign | Likely Benign | 0.161 | Likely Benign | 0.88 | Neutral | 0.888 | Possibly Damaging | 0.537 | Possibly Damaging | 4.23 | Benign | 0.81 | Tolerated | 3.61 | 5 | 0.1313 | 0.3363 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||
| c.458C>G | T153S 2D AIThe SynGAP1 missense variant T153S is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign based on the collective predictions, 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 Benign | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -1.890 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.50 | Neutral | 0.235 | Benign | 0.039 | Benign | 4.19 | Benign | 0.14 | Tolerated | 0.3756 | 0.2886 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.460A>C | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which 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 high‑accuracy predictors (five pathogenic vs four benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.097 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.460A>G | S154G 2D AIThe SynGAP1 missense variant S154G is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -5.482 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -0.83 | Neutral | 0.006 | Benign | 0.008 | Benign | 4.05 | Benign | 0.11 | Tolerated | 0.2790 | 0.3944 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.461G>A | S154N 2D AIThe SynGAP1 missense variant S154N is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools largely support a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. Only one tool, polyPhen‑2 HumDiv, predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) likewise indicates likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of ClinVar annotation or gnomAD observation. The variant is most likely benign based on predictions, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -6.604 | Likely Benign | 0.385 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -1.00 | Neutral | 0.900 | Possibly Damaging | 0.434 | Benign | 4.10 | Benign | 0.22 | Tolerated | 0.1545 | 0.4298 | 1 | 1 | -2.7 | 27.03 | |||||||||||||||||||||||||||||||||||||||
| c.461G>C | S154T 2D AIThe SynGAP1 missense variant S154T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv 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 confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -5.313 | Likely Benign | 0.155 | Likely Benign | Likely Benign | 0.167 | Likely Benign | -0.32 | Neutral | 0.900 | Possibly Damaging | 0.434 | Benign | 4.13 | Benign | 0.99 | Tolerated | 0.1686 | 0.5099 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.461G>T | S154I 2D  AIThe SynGAP1 missense variant S154I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic) and therefore unavailable as evidence. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not provided and is treated as unavailable. High‑accuracy predictions therefore indicate a benign outcome (AlphaMissense‑Optimized) with no decisive evidence from SGM Consensus or Foldetta. Overall, the variant is most likely benign, 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. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -10.061 | Likely Pathogenic | 0.665 | Likely Pathogenic | Likely Benign | 0.105 | Likely Benign | -2.24 | Neutral | 0.990 | Probably Damaging | 0.797 | Possibly Damaging | 4.03 | Benign | 0.07 | Tolerated | 0.0953 | 0.5123 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.462C>A | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (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, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy AlphaMissense‑Optimized also indicates pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.072 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.462C>G | S154R 2D AIThe SynGAP1 missense variant S154R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (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, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy AlphaMissense‑Optimized also indicates pathogenicity. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.508330 | Binding | 0.284 | 0.795 | 0.500 | -9.119 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 0.072 | Likely Benign | -1.73 | Neutral | 0.990 | Probably Damaging | 0.723 | Possibly Damaging | 4.10 | Benign | 0.14 | Tolerated | 0.0997 | 0.3298 | 0 | -1 | -3.7 | 69.11 | ||||||||||||||||||||||||||||||||||||||||
| c.472C>A | Q158K 2D AIThe SynGAP1 missense variant Q158K is not reported in ClinVar and has no entry in gnomAD, indicating it is not catalogued in these databases. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus indicates likely benign, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the computational evidence strongly suggests 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.795 | Likely Benign | 0.481 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -0.86 | Neutral | 0.276 | Benign | 0.121 | Benign | 4.20 | Benign | 0.15 | Tolerated | 0.1851 | 0.3869 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.472C>G | Q158E 2D AIThe SynGAP1 missense variant Q158E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only ESM1b predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign effect, and this 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -11.133 | Likely Pathogenic | 0.196 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.54 | Neutral | 0.143 | Benign | 0.078 | Benign | 4.20 | Benign | 0.09 | Tolerated | 0.1420 | 0.2223 | 2 | 2 | 0.0 | 0.98 | |||||||||||||||||||||||||||||||||||||||
| c.473A>G | Q158R 2D AIThe SynGAP1 missense variant Q158R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is uncertain. 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 | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -6.873 | Likely Benign | 0.438 | Ambiguous | Likely Benign | 0.090 | Likely Benign | -0.85 | Neutral | 0.276 | Benign | 0.121 | Benign | 4.14 | Benign | 0.11 | Tolerated | 0.1527 | 0.1498 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.474G>C | Q158H 2D  AIThe SynGAP1 missense variant Q158H is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, 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 Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -2.990 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.02 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.19 | Benign | 0.51 | Tolerated | 0.1403 | 0.3774 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.474G>T | Q158H 2D AIThe SynGAP1 missense variant Q158H is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the variant is most likely benign, 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 Benign | 0.480142 | Structured | 0.527565 | Binding | 0.286 | 0.750 | 0.375 | -2.990 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.084 | Likely Benign | 0.02 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.19 | Benign | 0.51 | Tolerated | 0.1403 | 0.3774 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.484C>A | R162S 2D AIThe SynGAP1 missense variant R162S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). AlphaMissense‑Optimized is currently Uncertain, and no Foldetta stability result is available. Overall, the majority of high‑accuracy and consensus predictions indicate a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | -1.395 | Likely Benign | 0.894 | Likely Pathogenic | Ambiguous | 0.191 | Likely Benign | -0.24 | Neutral | 0.487 | Possibly Damaging | 0.272 | Benign | 4.14 | Benign | 0.75 | Tolerated | 0.3080 | 0.4974 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||||||||||||
| c.484C>G | R162G 2D AIThe SynGAP1 missense variant R162G is listed in ClinVar (ID 2703066.0) with an uncertain significance status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta stability analysis is unavailable. Overall, the majority of predictions support a benign impact, and this 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 | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | Uncertain | 1 | -6.985 | Likely Benign | 0.664 | Likely Pathogenic | Likely Benign | 0.190 | Likely Benign | -0.73 | Neutral | 0.487 | Possibly Damaging | 0.272 | Benign | 4.09 | Benign | 0.78 | Tolerated | 3.74 | 4 | 0.3562 | 0.4308 | -2 | -3 | 4.1 | -99.14 | |||||||||||||||||||||||||||||||||||
| c.484C>T | R162C 2D  AIThe SynGAP1 missense variant R162C is listed in ClinVar as Pathogenic and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the available predictions are split evenly between benign and pathogenic, with no single method providing decisive evidence. Thus, the variant’s pathogenicity remains uncertain based on computational predictions, which contradicts the ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | Pathogenic | 2 | -8.157 | Likely Pathogenic | 0.787 | Likely Pathogenic | Ambiguous | 0.150 | Likely Benign | -2.05 | Neutral | 0.988 | Probably Damaging | 0.513 | Possibly Damaging | 4.00 | Benign | 0.11 | Tolerated | 3.74 | 4 | 0.3364 | 0.4292 | -4 | -3 | 7.0 | -53.05 | ||||||||||||||||||||||||||||||||||||
| c.485G>A | R162H 2D  AIThe SynGAP1 missense variant R162H is listed in ClinVar with an uncertain significance and is present in the gnomAD database (variant ID 6‑33432782‑G‑A). Functional prediction tools cluster into two groups: benign calls are made by REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls come from polyPhen‑2 (HumDiv and HumVar) and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign verdict. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, did not provide a result for this variant. Overall, the preponderance of evidence points to a benign effect, which does not contradict the ClinVar uncertain classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | Uncertain | 1 | 6-33432782-G-A | 2 | 1.24e-6 | -9.730 | Likely Pathogenic | 0.480 | Ambiguous | Likely Benign | 0.167 | Likely Benign | -1.13 | Neutral | 0.957 | Probably Damaging | 0.513 | Possibly Damaging | 4.03 | Benign | 0.12 | Tolerated | 3.74 | 4 | 0.2981 | 0.2872 | 2 | 0 | 1.3 | -19.05 | |||||||||||||||||||||||||||||||||
| c.485G>C | R162P 2D  AISynGAP1 missense variant R162P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool reports an uncertain result, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which combines FoldX‑MD and Rosetta stability outputs, has no available result for this variant. Consequently, the evidence is evenly divided: four tools support benign, four support pathogenic, and the remaining high‑accuracy methods provide no decisive signal. The variant is therefore not clearly benign or pathogenic based on current predictions, and this lack of consensus does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | -10.077 | Likely Pathogenic | 0.787 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | -1.50 | Neutral | 0.910 | Possibly Damaging | 0.578 | Possibly Damaging | 4.03 | Benign | 0.30 | Tolerated | 0.2192 | 0.5507 | 0 | -2 | 2.9 | -59.07 | ||||||||||||||||||||||||||||||||||||||||
| c.485G>T | R162L 2D  AIThe SynGAP1 missense variant R162L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM, giving six concordant benign calls. Two tools predict a pathogenic effect: ESM1b and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta data are unavailable. Overall, the majority of evidence points to a benign impact, 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. | 0.501700 | Disordered | 0.516348 | Binding | 0.315 | 0.692 | 0.250 | -9.952 | Likely Pathogenic | 0.840 | Likely Pathogenic | Ambiguous | 0.219 | Likely Benign | -1.83 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.05 | Benign | 0.15 | Tolerated | 0.1888 | 0.5894 | -3 | -2 | 8.3 | -43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.487T>C | F163L 2D  AIThe SynGAP1 missense variant F163L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus indicates a likely benign outcome; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not contradict the ClinVar status, which currently has no classification for F163L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.193 | Likely Benign | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 0.2191 | 0.3491 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.489C>A | F163L 2D AIThe SynGAP1 missense variant F163L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM‑Consensus indicates a likely benign outcome; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not contradict the ClinVar status, which currently has no classification for F163L. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 0.2191 | 0.3491 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.489C>G | F163L 2D AIThe SynGAP1 missense variant F163L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, six tools favor a benign outcome versus four favoring pathogenicity, and the high‑accuracy predictions are conflicting. Thus, the variant is most likely benign based on the current consensus, 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 | 0.433034 | Structured | 0.513928 | Binding | 0.325 | 0.686 | 0.375 | -6.380 | Likely Benign | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.190 | Likely Benign | -1.22 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 4.21 | Benign | 0.37 | Tolerated | 0.2191 | 0.3491 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.496G>A | A166T 2D AIThe SynGAP1 missense variant A166T is not reported in ClinVar and is absent from gnomAD. In silico prediction tools that assess sequence conservation and structural impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the change as benign. No tool in the dataset predicts pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign.” Foldetta results are not available. Overall, the consensus of all available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.505037 | Binding | 0.384 | 0.658 | 0.125 | -6.700 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -0.78 | Neutral | 0.399 | Benign | 0.273 | Benign | 4.10 | Benign | 0.31 | Tolerated | 0.1420 | 0.5134 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.502C>A | H168N 2D AIThe SynGAP1 missense variant H168N is not reported in ClinVar and is absent from gnomAD. All evaluated in‑silico predictors classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all return benign scores. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. No tools predict pathogenicity. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -4.764 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -0.14 | Neutral | 0.016 | Benign | 0.015 | Benign | 4.29 | Benign | 0.60 | Tolerated | 0.1516 | 0.2589 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||||||||||||
| c.502C>G | H168D 2D AIThe SynGAP1 missense variant H168D is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign consensus, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.433034 | Structured | 0.502450 | Binding | 0.402 | 0.678 | 0.125 | -8.519 | Likely Pathogenic | 0.481 | Ambiguous | Likely Benign | 0.131 | Likely Benign | -1.24 | Neutral | 0.016 | Benign | 0.021 | Benign | 4.24 | Benign | 0.08 | Tolerated | 0.2365 | 0.2017 | 1 | -1 | -0.3 | -22.05 | ||||||||||||||||||||||||||||||||||||||||
| c.507C>A | D169E 2D AIThe SynGAP1 missense variant D169E is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -4.571 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.030 | Likely Benign | -1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.23 | Benign | 0.42 | Tolerated | 0.1636 | 0.7316 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.507C>G | D169E 2D AIThe SynGAP1 missense variant D169E is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions points to a benign impact, and this conclusion is consistent with the lack of a ClinVar classification, so there is no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.418646 | Structured | 0.497160 | Uncertain | 0.420 | 0.675 | 0.125 | -4.571 | Likely Benign | 0.249 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.31 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.23 | Benign | 0.42 | Tolerated | 0.1636 | 0.7316 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.511G>T | A171S 2D AIThe SynGAP1 missense variant A171S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.492272 | Uncertain | 0.358 | 0.652 | 0.375 | -0.011 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.054 | Likely Benign | 0.40 | Neutral | 0.002 | Benign | 0.001 | Benign | 4.33 | Benign | 0.91 | Tolerated | 0.2221 | 0.4383 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||||||||||||
| c.517C>A | L173M 2D AIThe SynGAP1 missense variant L173M is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools—AlphaMissense‑Default and ESM1b—return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields two benign and two uncertain calls, and Foldetta data are unavailable. Overall, the balance of evidence favors a benign classification, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -7.149 | In-Between | 0.534 | Ambiguous | Likely Benign | 0.129 | Likely Benign | -0.61 | Neutral | 0.940 | Possibly Damaging | 0.564 | Possibly Damaging | 3.96 | Benign | 0.20 | Tolerated | 0.0648 | 0.3123 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||||||||||||
| c.517C>G | L173V 2D AIThe SynGAP1 missense variant L173V is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority vote. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -8.320 | Likely Pathogenic | 0.495 | Ambiguous | Likely Benign | 0.100 | Likely Benign | -0.95 | Neutral | 0.131 | Benign | 0.058 | Benign | 4.05 | Benign | 0.22 | Tolerated | 0.1343 | 0.3217 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.518T>A | L173Q 2D AIThe SynGAP1 missense variant L173Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple in silico predictors and the SGM‑Consensus indicates that the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -5.605 | Likely Benign | 0.850 | Likely Pathogenic | Ambiguous | 0.133 | Likely Benign | -1.72 | Neutral | 0.022 | Benign | 0.022 | Benign | 3.94 | Benign | 0.08 | Tolerated | 0.1028 | 0.0919 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.518T>C | L173P 2D AIThe SynGAP1 missense variant L173P is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 because it yields a 2‑to‑2 split; Foldetta results are not available. Consequently, the computational evidence is evenly divided, providing no clear advantage for either benign or pathogenic classification. The variant is therefore most likely inconclusive based on current predictions, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -8.758 | Likely Pathogenic | 0.918 | Likely Pathogenic | Ambiguous | 0.135 | Likely Benign | -2.38 | Neutral | 0.838 | Possibly Damaging | 0.466 | Possibly Damaging | 3.92 | Benign | 0.15 | Tolerated | 0.3318 | 0.1382 | -3 | -3 | -5.4 | -16.04 | ||||||||||||||||||||||||||||||||||||||||
| c.518T>G | L173R 2D AIThe SynGAP1 missense variant L173R is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of consensus tools lean toward a benign interpretation, and there is no ClinVar evidence to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.534167 | Disordered | 0.491566 | Uncertain | 0.390 | 0.631 | 0.375 | -9.524 | Likely Pathogenic | 0.904 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -1.63 | Neutral | 0.561 | Possibly Damaging | 0.178 | Benign | 3.95 | Benign | 0.08 | Tolerated | 0.1258 | 0.0761 | -3 | -2 | -8.3 | 43.03 | ||||||||||||||||||||||||||||||||||||||||
| c.520A>C | M174L 2D AIThe SynGAP1 missense variant M174L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default 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 majority of evidence points to a benign impact for M174L. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -5.839 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | -0.82 | Neutral | 0.055 | Benign | 0.011 | Benign | 4.21 | Benign | 0.46 | Tolerated | 0.1335 | 0.4545 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.520A>T | M174L 2D AIThe SynGAP1 missense variant M174L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only AlphaMissense‑Default 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 majority of evidence points to a benign impact for M174L. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -5.839 | Likely Benign | 0.608 | Likely Pathogenic | Likely Benign | 0.192 | Likely Benign | -0.82 | Neutral | 0.055 | Benign | 0.011 | Benign | 4.21 | Benign | 0.46 | Tolerated | 0.1335 | 0.4545 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||||||||||||
| c.522G>A | M174I 2D AIThe SynGAP1 missense variant M174I is listed in gnomAD (ID 6‑33435164‑G‑A) but has no ClinVar record. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; pathogenic predictions come from ESM1b and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2) and Foldetta results are unavailable. Overall, six tools predict benign while only two predict pathogenic, and the only high‑accuracy pathogenic call is from AlphaMissense‑Optimized. Thus, the variant is most likely benign based on the preponderance of evidence, 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. | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | 6-33435164-G-A | 4 | 2.48e-6 | -8.732 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.120 | Likely Benign | -1.63 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.10 | Benign | 0.07 | Tolerated | 3.61 | 5 | 0.1191 | 0.3469 | 1 | 2 | 2.6 | -18.03 | |||||||||||||||||||||||||||||||||||
| c.522G>C | M174I 2D AIThe SynGAP1 missense variant M174I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta’s stability assessment is unavailable. Overall, the majority of standard predictors favor a benign outcome, and the high‑accuracy predictions do not override this trend. Thus, 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. | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -8.732 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.120 | Likely Benign | -1.63 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.10 | Benign | 0.07 | Tolerated | 3.61 | 5 | 0.1191 | 0.3469 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.522G>T | M174I 2D AIThe SynGAP1 missense variant M174I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta data are unavailable. Overall, the majority of standard predictors indicate a benign impact, while the single high‑accuracy tool suggests pathogenicity but is not supported by consensus or folding‑stability evidence. Thus, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.661982 | Disordered | 0.485854 | Uncertain | 0.373 | 0.620 | 0.375 | -8.732 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.120 | Likely Benign | -1.63 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.10 | Benign | 0.07 | Tolerated | 3.61 | 5 | 0.1191 | 0.3469 | 1 | 2 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||||||||||
| c.523C>A | Q175K 2D AIThe SynGAP1 missense variant Q175K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM. Only AlphaMissense‑Default predicts a pathogenic outcome, while AlphaMissense‑Optimized is uncertain. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized remains uncertain, SGM‑Consensus is benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for Q175K, 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 | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -5.908 | Likely Benign | 0.826 | Likely Pathogenic | Ambiguous | 0.202 | Likely Benign | -0.89 | Neutral | 0.118 | Benign | 0.039 | Benign | 4.18 | Benign | 0.37 | Tolerated | 0.1655 | 0.3723 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||||||||||||
| c.523C>G | Q175E 2D AIThe SynGAP1 missense variant Q175E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a benign bias: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, whereas ESM1b predicts it to be pathogenic. AlphaMissense‑Default remains uncertain. High‑accuracy assessment further supports a benign outcome: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta stability analysis is unavailable. Consequently, the overall evidence points to a benign effect for Q175E. This conclusion is consistent with the absence of a ClinVar assertion, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -11.035 | Likely Pathogenic | 0.502 | Ambiguous | Likely Benign | 0.149 | Likely Benign | -0.68 | Neutral | 0.118 | Benign | 0.039 | Benign | 4.17 | Benign | 0.40 | Tolerated | 0.1351 | 0.2028 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||||||||||||
| c.524A>C | Q175P 2D AIThe SynGAP1 missense variant Q175P is reported in gnomAD (ID 6‑33435166‑A‑C) but has no ClinVar entry. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all score the substitution as benign. The consensus from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy predictors corroborate this assessment: AlphaMissense‑Optimized predicts a benign outcome, and the SGM‑Consensus (majority vote) confirms a likely benign status. No high‑accuracy folding‑stability analysis (Foldetta) is available for this residue, so stability effects remain unassessed. Overall, the collective evidence points to a benign impact for Q175P, and this conclusion is consistent with the absence of a pathogenic ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | 6-33435166-A-C | 1 | 6.20e-7 | -6.995 | Likely Benign | 0.432 | Ambiguous | Likely Benign | 0.211 | Likely Benign | 1.55 | Neutral | 0.396 | Benign | 0.188 | Benign | 4.20 | Benign | 1.00 | Tolerated | 3.61 | 5 | 0.2075 | 0.4584 | -1 | 0 | 1.9 | -31.01 | ||||||||||||||||||||||||||||||||||
| c.524A>G | Q175R 2D AIThe SynGAP1 missense variant Q175R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. The only tool that predicts a pathogenic outcome is 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, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, 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 Benign | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -5.785 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.194 | Likely Benign | -1.29 | Neutral | 0.012 | Benign | 0.006 | Benign | 4.14 | Benign | 0.26 | Tolerated | 0.1485 | 0.1352 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||||||||||||
| c.524A>T | Q175L 2D AIThe SynGAP1 missense variant Q175L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, seven tools favor benign while two favor pathogenic, with no ClinVar evidence to contradict this. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -8.699 | Likely Pathogenic | 0.579 | Likely Pathogenic | Likely Benign | 0.188 | Likely Benign | -2.46 | Neutral | 0.118 | Benign | 0.039 | Benign | 4.10 | Benign | 0.14 | Tolerated | 0.0647 | 0.5109 | -2 | -2 | 7.3 | -14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.525A>C | Q175H 2D AIThe SynGAP1 missense variant Q175H has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic 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 “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the balance of evidence favors a benign classification, 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 | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -6.635 | Likely Benign | 0.824 | Likely Pathogenic | Ambiguous | 0.185 | Likely Benign | -1.52 | Neutral | 0.875 | Possibly Damaging | 0.459 | Possibly Damaging | 4.09 | Benign | 0.10 | Tolerated | 0.1273 | 0.3411 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.525A>T | Q175H 2D AIThe SynGAP1 missense variant Q175H has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; no Foldetta stability data are available. Overall, the balance of evidence favors a benign classification, 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 | 0.653063 | Disordered | 0.474689 | Uncertain | 0.367 | 0.618 | 0.375 | -6.635 | Likely Benign | 0.824 | Likely Pathogenic | Ambiguous | 0.185 | Likely Benign | -1.52 | Neutral | 0.875 | Possibly Damaging | 0.459 | Possibly Damaging | 4.09 | Benign | 0.10 | Tolerated | 0.1273 | 0.3411 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.526A>C | S176R 2D AIThe SynGAP1 missense variant S176R 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, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains likely benign; Foldetta results are unavailable. Overall, the balance of evidence favors a benign interpretation, and this assessment does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | Uncertain | 1 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.247 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||
| c.526A>G | S176G 2D AIThe SynGAP1 missense variant S176G is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435168‑A‑G). Consensus among most in silico predictors is benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all report a benign effect. No tool predicts pathogenicity. Two predictors are inconclusive: ESM1b and AlphaMissense‑Default, which are grouped under uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) remains uncertain, and Foldetta stability analysis is unavailable. Overall, the computational evidence overwhelmingly favors 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. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | Uncertain | 1 | 6-33435168-A-G | 1 | 6.20e-7 | -7.541 | In-Between | 0.360 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.08 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.08 | Benign | 0.22 | Tolerated | 3.54 | 6 | 0.2361 | 0.3414 | 0 | 1 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||
| c.527G>A | S176N 2D AIThe SynGAP1 missense variant S176N is catalogued in gnomAD (ID 6‑33435169‑G‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only AlphaMissense‑Default predicts a pathogenic outcome. 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 reported). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | 6-33435169-G-A | 1 | 6.20e-7 | -6.286 | Likely Benign | 0.594 | Likely Pathogenic | Likely Benign | 0.070 | Likely Benign | -0.56 | Neutral | 0.421 | Benign | 0.080 | Benign | 4.10 | Benign | 0.22 | Tolerated | 3.54 | 6 | 0.0996 | 0.3930 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||
| c.527G>C | S176T 2D AIThe SynGAP1 missense variant S176T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; AlphaMissense‑Default is 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, has no available result for this variant. Overall, the consensus of available predictions indicates that the variant is most likely benign, 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 | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -3.682 | Likely Benign | 0.351 | Ambiguous | Likely Benign | 0.045 | Likely Benign | -0.73 | Neutral | 0.421 | Benign | 0.054 | Benign | 4.09 | Benign | 0.19 | Tolerated | 0.1103 | 0.4979 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.527G>T | S176I 2D AIThe SynGAP1 missense variant S176I is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a 2‑vs‑2 split, and Foldetta results are not available. Overall, the majority of evidence (six benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar, as the variant has no ClinVar entry. 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. | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -10.247 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.152 | Likely Benign | -2.03 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.04 | Benign | 0.06 | Tolerated | 0.0790 | 0.5290 | -1 | -2 | 5.3 | 26.08 | ||||||||||||||||||||||||||||||||||||||||
| c.528C>A | S176R 2D AIThe SynGAP1 missense variant S176R has no ClinVar record and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized reports a pathogenic outcome, whereas the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; Foldetta data are unavailable. Overall, the majority of predictions support a benign interpretation, and there is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.528C>G | S176R 2D AIThe SynGAP1 missense variant S176R has no ClinVar record and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (majority vote) all classify the change as benign or likely benign. In contrast, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized reports a pathogenic outcome, whereas the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; Foldetta data are unavailable. Overall, the majority of predictions support a benign interpretation, and there is no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.562014 | Disordered | 0.466016 | Uncertain | 0.380 | 0.597 | 0.375 | -6.492 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.230 | Likely Benign | 0.94 | Neutral | 0.718 | Possibly Damaging | 0.168 | Benign | 4.16 | Benign | 0.87 | Tolerated | 0.0697 | 0.3160 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||||||||||||
| c.529T>A | F177I 2D  AIThe SynGAP1 missense variant F177I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. three pathogenic) suggest a benign impact, though the presence of pathogenic signals from high‑accuracy tools introduces uncertainty. The variant is most likely benign based on the current evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -10.208 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.148 | Likely Benign | -0.60 | Neutral | 0.131 | Benign | 0.058 | Benign | 4.18 | Benign | 0.11 | Tolerated | 0.2282 | 0.3299 | 1 | 0 | 1.7 | -34.02 | ||||||||||||||||||||||||||||||||||||||||
| c.529T>C | F177L 2D AIThe SynGAP1 missense variant F177L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.184 | Likely Benign | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 0.2376 | 0.4280 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.529T>G | F177V 2D  AIThe SynGAP1 missense variant F177V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Overall, the majority of standard predictors favor a benign outcome, but the optimized AlphaMissense model and ESM1b suggest potential pathogenicity. Thus, the variant is most likely benign based on the collective evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -11.582 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -1.26 | Neutral | 0.028 | Benign | 0.009 | Benign | 4.18 | Benign | 0.06 | Tolerated | 0.2454 | 0.3526 | -1 | -1 | 1.4 | -48.04 | ||||||||||||||||||||||||||||||||||||||||
| c.530T>A | F177Y 2D  AIThe SynGAP1 missense variant F177Y is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized tool returns an uncertain result, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2). Foldetta, a protein‑folding stability method, has no available output for this variant. Overall, the majority of consensus tools lean toward a benign interpretation, and there is no ClinVar record to contradict 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. | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -9.643 | Likely Pathogenic | 0.932 | Likely Pathogenic | Ambiguous | 0.138 | Likely Benign | -1.17 | Neutral | 0.818 | Possibly Damaging | 0.201 | Benign | 4.08 | Benign | 0.07 | Tolerated | 0.1511 | 0.2756 | 7 | 3 | -4.1 | 16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.531T>A | F177L 2D AIThe SynGAP1 missense variant F177L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.173 | Likely Benign | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 0.2376 | 0.4280 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.531T>G | F177L 2D AIThe SynGAP1 missense variant F177L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are AlphaMissense‑Default and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence (seven benign predictions versus two pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.461817 | Uncertain | 0.357 | 0.598 | 0.500 | -5.564 | Likely Benign | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.173 | Likely Benign | 0.24 | Neutral | 0.022 | Benign | 0.022 | Benign | 4.41 | Benign | 1.00 | Tolerated | 0.2376 | 0.4280 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||||||||||||
| c.533A>G | K178R 2D AIThe SynGAP1 missense variant K178R is reported in gnomAD (ID 6‑33435175‑A‑G) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumDiv predicts it as pathogenic, while the consensus score from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM Consensus also indicates likely benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for K178R, and this conclusion is not contradicted by any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.497853 | Structured | 0.455271 | Uncertain | 0.354 | 0.622 | 0.375 | 6-33435175-A-G | 1 | 6.20e-7 | -4.398 | Likely Benign | 0.281 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.62 | Neutral | 0.905 | Possibly Damaging | 0.393 | Benign | 3.98 | Benign | 0.14 | Tolerated | 3.54 | 6 | 0.5403 | 0.1131 | Weaken | 2 | 3 | -0.6 | 28.01 | |||||||||||||||||||||||||||||||||
| c.536A>C | E179A 2D AISynGAP1 E179A is not reported in ClinVar and has no entry in gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; pathogenic predictions come from PROVEAN, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is Uncertain, SGM‑Consensus is Likely Pathogenic, and Foldetta data are unavailable. Overall, the majority of individual predictors lean benign, yet the consensus and high‑accuracy tools indicate pathogenicity, leaving the variant’s effect ambiguous. The predictions do not contradict ClinVar status, which has no entry for this variant. Based on the aggregate predictions, the variant is most likely benign, although the SGM‑Consensus and high‑accuracy tools raise a pathogenic signal, making the overall assessment inconclusive. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -9.862 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | -3.61 | Deleterious | 0.131 | Benign | 0.079 | Benign | 4.01 | Benign | 0.09 | Tolerated | 0.4465 | 0.7186 | 0 | -1 | 5.3 | -58.04 | |||||||||||||||||||||||||||||||||||||||
| c.536A>G | E179G 2D  AIThe SynGAP1 missense variant E179G is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Among the available in‑silico predictors, six tools (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM) unanimously predict a benign effect, whereas two tools (PROVEAN and AlphaMissense‑Default) predict pathogenicity. High‑accuracy predictors give no definitive verdict: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs. two benign votes); and Foldetta results are unavailable. Consequently, the overall evidence leans toward a benign interpretation, with no conflict with the lack of ClinVar annotation. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.517562 | Disordered | 0.448169 | Uncertain | 0.329 | 0.635 | 0.500 | -6.527 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.158 | Likely Benign | -4.24 | Deleterious | 0.001 | Benign | 0.004 | Benign | 3.97 | Benign | 0.09 | Tolerated | 0.3273 | 0.6425 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||||||||||||
| c.542A>G | H181R 2D AIThe SynGAP1 missense variant H181R 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, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv 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 likewise indicates 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -3.668 | Likely Benign | 0.521 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -0.11 | Neutral | 0.818 | Possibly Damaging | 0.188 | Benign | 4.35 | Benign | 1.00 | Tolerated | 0.1585 | 0.1782 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.543C>A | H181Q 2D AIThe SynGAP1 missense variant H181Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic, two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools therefore give a benign prediction from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and no Foldetta data. Overall, the majority of predictions (six benign vs. three pathogenic) indicate that the variant is most likely benign, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -9.577 | Likely Pathogenic | 0.692 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -1.45 | Neutral | 0.940 | Possibly Damaging | 0.360 | Benign | 4.19 | Benign | 0.09 | Tolerated | 0.1241 | 0.2835 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.543C>G | H181Q 2D AIThe SynGAP1 H181Q 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, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which takes a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic vs two benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. High‑accuracy tools therefore give a benign prediction from AlphaMissense‑Optimized, an inconclusive SGM Consensus, and an unavailable Foldetta result. Overall, the majority of predictions (six benign vs three pathogenic) indicate that the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.505461 | Disordered | 0.439530 | Uncertain | 0.294 | 0.616 | 0.500 | -9.577 | Likely Pathogenic | 0.692 | Likely Pathogenic | Likely Benign | 0.125 | Likely Benign | -1.45 | Neutral | 0.940 | Possibly Damaging | 0.360 | Benign | 4.19 | Benign | 0.09 | Tolerated | 0.1241 | 0.2835 | 3 | 0 | -0.3 | -9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.548A>G | H183R 2D AIThe SynGAP1 H183R missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic and the SGM‑Consensus (majority vote) also pathogenic; Foldetta stability analysis is unavailable. Based on the majority of computational evidence, 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 | 0.476583 | Structured | 0.432952 | Uncertain | 0.421 | 0.622 | 0.500 | -10.937 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.368 | Likely Benign | -5.43 | Deleterious | 0.596 | Possibly Damaging | 0.142 | Benign | 3.90 | Benign | 0.13 | Tolerated | 0.1915 | 0.2249 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||||||||||||
| c.563G>C | S188T 2D AIThe SynGAP1 missense variant S188T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain predictions come from ESM1b and AlphaMissense‑Optimized. High‑accuracy assessment shows that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign (two benign versus one pathogenic vote). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion does not contradict any ClinVar annotation, as none exists for S188T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.490133 | Structured | 0.428502 | Uncertain | 0.298 | 0.603 | 0.500 | -7.906 | In-Between | 0.801 | Likely Pathogenic | Ambiguous | 0.124 | Likely Benign | -1.97 | Neutral | 0.948 | Possibly Damaging | 0.484 | Possibly Damaging | 3.92 | Benign | 0.13 | Tolerated | 0.1491 | 0.7492 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.565C>G | P189A 2D AIThe SynGAP1 missense variant P189A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (two pathogenic, two benign), and Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. four benign) and the pathogenic call from AlphaMissense‑Optimized suggest that the variant is most likely pathogenic. 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. | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -4.998 | Likely Benign | 0.974 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | -5.46 | Deleterious | 0.941 | Possibly Damaging | 0.607 | Possibly Damaging | 4.07 | Benign | 0.07 | Tolerated | 0.3719 | 0.6209 | 1 | -1 | 3.4 | -26.04 | ||||||||||||||||||||||||||||||||||||||||
| c.565C>T | P189S 2D AIThe SynGAP1 missense variant P189S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. Tools that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also favors pathogenicity (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of computational evidence indicates 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. | 0.497853 | Structured | 0.428590 | Uncertain | 0.331 | 0.602 | 0.250 | -7.191 | In-Between | 0.992 | Likely Pathogenic | Likely Pathogenic | 0.211 | Likely Benign | -5.23 | Deleterious | 0.941 | Possibly Damaging | 0.531 | Possibly Damaging | 4.09 | Benign | 0.15 | Tolerated | 0.3626 | 0.6460 | 1 | -1 | 0.8 | -10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.566C>T | P189L 2D AIThe SynGAP1 missense variant P189L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM. In contrast, a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) all indicate likely pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors points to a pathogenic classification, with no ClinVar record to contradict this assessment. 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 | -10.132 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 0.290 | Likely Benign | -7.28 | Deleterious | 0.991 | Probably Damaging | 0.781 | Possibly Damaging | 4.04 | Benign | 0.17 | Tolerated | 0.2283 | 0.7378 | -3 | -3 | 5.4 | 16.04 | |||||||||||||||||||||||||||||||||||||||
| c.568A>G | S190G 2D AIThe SynGAP1 missense variant S190G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized reports a benign outcome, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” verdict. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -5.440 | Likely Benign | 0.321 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -1.26 | Neutral | 0.243 | Benign | 0.079 | Benign | 4.11 | Benign | 0.19 | Tolerated | 0.2780 | 0.4765 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||||||||||||
| c.568A>T | S190C 2D AIThe SynGAP1 missense variant S190C 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -6.696 | Likely Benign | 0.617 | Likely Pathogenic | Likely Benign | 0.107 | Likely Benign | -2.04 | Neutral | 0.992 | Probably Damaging | 0.707 | Possibly Damaging | 4.01 | Benign | 0.23 | Tolerated | 0.0937 | 0.6667 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.569G>A | S190N 2D AIThe SynGAP1 missense variant S190N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM, while polyPhen‑2 HumDiv and AlphaMissense‑Default predict a pathogenic outcome. The remaining tools, ESM1b and AlphaMissense‑Optimized, are uncertain. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized is uncertain; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign (two benign votes versus one pathogenic and one uncertain); and Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -7.497 | In-Between | 0.838 | Likely Pathogenic | Ambiguous | 0.160 | Likely Benign | -1.73 | Neutral | 0.759 | Possibly Damaging | 0.202 | Benign | 4.06 | Benign | 0.08 | Tolerated | 0.1119 | 0.5285 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||||||||||||
| c.569G>C | S190T 2D AIThe SynGAP1 missense variant S190T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus confirms Likely 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 status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.422041 | Structured | 0.428613 | Uncertain | 0.338 | 0.615 | 0.250 | -6.870 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.114 | Likely Benign | -1.31 | Neutral | 0.608 | Possibly Damaging | 0.108 | Benign | 4.08 | Benign | 0.20 | Tolerated | 0.1294 | 0.6920 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.574G>A | A192T 2D AIThe SynGAP1 missense variant A192T has no ClinVar record (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic, 1 uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM Consensus remains benign; Foldetta results are unavailable. Overall, the balance of evidence leans toward 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. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.562 | In-Between | 0.958 | Likely Pathogenic | Likely Pathogenic | 0.089 | Likely Benign | -2.46 | Neutral | 0.978 | Probably Damaging | 0.714 | Possibly Damaging | 3.96 | Benign | 0.34 | Tolerated | 0.1148 | 0.5343 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.574G>T | A192S 2D AIThe SynGAP1 missense variant A192S is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv 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) also favors benign, while Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.969 | In-Between | 0.757 | Likely Pathogenic | Likely Benign | 0.118 | Likely Benign | -2.01 | Neutral | 0.633 | Possibly Damaging | 0.171 | Benign | 3.98 | Benign | 0.12 | Tolerated | 0.2365 | 0.3764 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||||||||
| c.575C>T | A192V 2D AIThe SynGAP1 missense variant A192V is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. ESM1b remains uncertain. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority (2 pathogenic vs. 1 benign, 1 uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that A192V is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.422041 | Structured | 0.428195 | Uncertain | 0.321 | 0.589 | 0.125 | -7.464 | In-Between | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.172 | Likely Benign | -2.66 | Deleterious | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.01 | Benign | 0.11 | Tolerated | 0.0904 | 0.5066 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||||
| c.577G>A | A193T 2D AIThe SynGAP1 missense variant A193T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus as Likely Benign; Foldetta results are not available. 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 | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -4.973 | Likely Benign | 0.789 | Likely Pathogenic | Ambiguous | 0.208 | Likely Benign | -1.36 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 4.07 | Benign | 0.21 | Tolerated | 0.1452 | 0.7231 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||||||||||||
| c.578C>T | A193V 2D AIThe SynGAP1 A193V 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, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign (three benign votes versus one pathogenic). 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 annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.429200 | Structured | 0.428386 | Uncertain | 0.310 | 0.577 | 0.125 | -3.548 | Likely Benign | 0.744 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | 0.52 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 4.30 | Benign | 1.00 | Tolerated | 0.1169 | 0.6775 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||||||||||||
| c.583G>A | A195T 2D AIThe SynGAP1 missense variant A195T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The remaining tools, ESM1b and AlphaMissense‑Optimized, return uncertain results. High‑accuracy assessment shows that the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign (2 benign vs. 1 pathogenic, 1 uncertain). Foldetta, which would provide a protein‑folding stability estimate, has no available output for this variant. Overall, the preponderance of evidence indicates that A195T is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -7.060 | In-Between | 0.883 | Likely Pathogenic | Ambiguous | 0.085 | Likely Benign | -2.09 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 4.08 | Benign | 0.14 | Tolerated | 0.0937 | 0.6006 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||||||||||||
| c.583G>T | A195S 2D AIThe SynGAP1 missense variant A195S is listed in gnomAD (6‑33435225‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority of the four high‑accuracy predictors) also indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the available predictions points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | 6-33435225-G-T | 1 | 6.20e-7 | -4.936 | Likely Benign | 0.618 | Likely Pathogenic | Likely Benign | 0.078 | Likely Benign | -1.13 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.10 | Benign | 0.08 | Tolerated | 3.54 | 6 | 0.1846 | 0.4427 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||||||
| c.584C>T | A195V 2D AIThe SynGAP1 missense variant A195V is not 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), SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default. High‑accuracy methods give no definitive verdict: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign votes), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, 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. | 0.346032 | Structured | 0.430388 | Uncertain | 0.363 | 0.533 | 0.125 | -5.830 | Likely Benign | 0.924 | Likely Pathogenic | Ambiguous | 0.210 | Likely Benign | -2.63 | Deleterious | 0.384 | Benign | 0.070 | Benign | 4.05 | Benign | 0.12 | Tolerated | 0.0782 | 0.5560 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||||||||||||
| c.591G>C | E197D 2D AIThe SynGAP1 missense variant E197D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are unavailable. Overall, the consensus of all available predictions strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | 0.784 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.81 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.66 | Benign | 1.00 | Tolerated | 0.1579 | 0.3345 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.591G>T | E197D 2D AIThe SynGAP1 missense variant E197D is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta results are unavailable. Overall, the consensus of all available predictions strongly supports a benign classification, and this is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.349426 | Structured | 0.431896 | Uncertain | 0.452 | 0.492 | 0.125 | 0.784 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.066 | Likely Benign | 1.81 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.66 | Benign | 1.00 | Tolerated | 0.1579 | 0.3345 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||||||||||||
| c.595A>C | N199H 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No predictions are missing or inconclusive. Overall, the majority of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which contains no pathogenic assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -6.387 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.17 | Likely Benign | 0.1 | 0.15 | Likely Benign | 0.16 | Likely Benign | 0.20 | Likely Benign | 0.064 | Likely Benign | -1.99 | Neutral | 0.952 | Possibly Damaging | 0.496 | Possibly Damaging | 4.17 | Benign | 0.08 | Tolerated | 0.0879 | 0.5635 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.595A>G | N199D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus classify the variant as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a benign effect. The only inconclusive results come from ESM1b and Rosetta, which are treated as unavailable. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign outcome. 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 | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -7.874 | In-Between | 0.338 | Likely Benign | Likely Benign | -0.14 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.41 | Likely Benign | 0.13 | Likely Benign | 0.028 | Likely Benign | -1.41 | Neutral | 0.276 | Benign | 0.062 | Benign | 4.22 | Benign | 0.35 | Tolerated | 0.1516 | 0.3514 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.596A>C | N199T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify it as benign or likely benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -4.123 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.2 | -0.10 | Likely Benign | 0.03 | Likely Benign | -0.04 | Likely Benign | 0.025 | Likely Benign | -0.82 | Neutral | 0.002 | Benign | 0.003 | Benign | 4.24 | Benign | 0.10 | Tolerated | 0.0862 | 0.6186 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.596A>G | N199S 2D AIThe SynGAP1 missense variant N199S 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 benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote) indicates likely benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the variant is most likely benign, and this prediction does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -0.268 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.08 | Likely Benign | 0.4 | -0.08 | Likely Benign | 0.00 | Likely Benign | -0.44 | Likely Benign | 0.040 | Likely Benign | 0.09 | Neutral | 0.160 | Benign | 0.045 | Benign | 4.36 | Benign | 0.57 | Tolerated | 0.2601 | 0.6023 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.597C>A | N199K 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant N199K is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign. Only ESM1b and AlphaMissense‑Default predict pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the preponderance of evidence supports a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | Uncertain | 1 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | 0.024 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 0.1399 | 0.5218 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||||||
| c.597C>G | N199K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N199K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Overall, the majority of evidence (10 benign vs. 2 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. | PH | 0.390993 | Structured | 0.431347 | Uncertain | 0.571 | 0.473 | 0.125 | -8.198 | Likely Pathogenic | 0.686 | Likely Pathogenic | Likely Benign | -0.19 | Likely Benign | 0.1 | 0.03 | Likely Benign | -0.08 | Likely Benign | 0.33 | Likely Benign | 0.024 | Likely Benign | -1.48 | Neutral | 0.276 | Benign | 0.083 | Benign | 4.27 | Benign | 0.13 | Tolerated | 3.47 | 9 | 0.1399 | 0.5218 | 1 | 0 | -0.4 | 14.07 | 207.8 | 21.5 | -0.1 | 1.5 | 0.1 | 0.0 | X | Uncertain | Asn199, located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by a positively charged lysine. On the protein surface, both the carboxamide group of Asn199 and the amino group of Lys199 side chains can form hydrogen bonds with the backbone carbonyl groups of residues (e.g., Ala249) at the end of an α helix (res. Ala236-Lys251). However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||||||||
| c.598T>A | L200M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200M is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign outcome. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus, derived from the four high‑confidence predictors, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Taken together, the overwhelming majority of evidence supports a benign classification for L200M, and this conclusion is consistent with the absence of a ClinVar entry. Thus, the variant is most likely benign, and this assessment does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -4.107 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.08 | Likely Benign | 0.1 | 0.41 | Likely Benign | 0.25 | Likely Benign | -0.25 | Likely Benign | 0.139 | Likely Benign | 0.47 | Neutral | 0.997 | Probably Damaging | 0.960 | Probably Damaging | 4.11 | Benign | 0.31 | Tolerated | 0.0751 | 0.3511 | 4 | 2 | -1.9 | 18.03 | |||||||||||||||||||||||||||||
| c.598T>G | L200V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L200V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and the Foldetta stability assessment. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as pathogenic. Overall, the majority of evidence points to a benign effect; there is no ClinVar annotation to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -6.917 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 2.15 | Destabilizing | 0.2 | 1.85 | Ambiguous | 2.00 | Destabilizing | 0.92 | Ambiguous | 0.098 | Likely Benign | -1.07 | Neutral | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 4.09 | Benign | 0.24 | Tolerated | 0.1593 | 0.3607 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.599T>C | L200S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 L200S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 vs 2). High‑accuracy methods give a pathogenic signal from Foldetta (protein‑folding stability analysis) while AlphaMissense‑Optimized is uncertain and thus not considered evidence. Overall, the majority of available predictions (10 pathogenic vs 4 benign) indicate a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -10.755 | Likely Pathogenic | 0.807 | Likely Pathogenic | Ambiguous | 2.72 | Destabilizing | 0.1 | 3.38 | Destabilizing | 3.05 | Destabilizing | 1.43 | Destabilizing | 0.141 | Likely Benign | -1.96 | Neutral | 0.970 | Probably Damaging | 0.683 | Possibly Damaging | 4.05 | Benign | 0.06 | Tolerated | 0.3279 | 0.0575 | -3 | -2 | -4.6 | -26.08 | ||||||||||||||||||||||||||||||
| c.600G>C | L200F 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L200F is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33435242‑G‑C). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | Uncertain | 1 | 6-33435242-G-C | 2 | 1.24e-6 | -7.606 | In-Between | 0.592 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.5 | 1.45 | Ambiguous | 1.23 | Ambiguous | 0.43 | Likely Benign | 0.094 | Likely Benign | -1.97 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.02 | Benign | 0.17 | Tolerated | 3.46 | 9 | 0.0640 | 0.3120 | 2 | 0 | -1.0 | 34.02 | 250.4 | -15.1 | 0.6 | 0.2 | 0.5 | 0.0 | X | Uncertain | Leu200, a hydrophobic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another hydrophobic residue, phenylalanine. Both the phenyl group of Phe200 and the branched iso-butyl hydrocarbon sidechain of Leu200 occupy an inward hydrophobic niche (e.g., Leu246, Val222, Phe231) during the simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||||
| c.600G>T | L200F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L200F missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, ESM1b, Foldetta) returned uncertain results and are not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (benign)—is benign; Foldetta remains uncertain and is treated as unavailable. Overall, the balance of evidence (six benign vs. three pathogenic predictions, with a benign consensus from high‑accuracy methods) indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428168 | Uncertain | 0.687 | 0.453 | 0.125 | -7.606 | In-Between | 0.592 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.5 | 1.45 | Ambiguous | 1.23 | Ambiguous | 0.43 | Likely Benign | 0.094 | Likely Benign | -1.97 | Neutral | 0.997 | Probably Damaging | 0.916 | Probably Damaging | 4.02 | Benign | 0.17 | Tolerated | 3.46 | 9 | 0.0640 | 0.3120 | 2 | 0 | -1.0 | 34.02 | 250.4 | -15.1 | 0.6 | 0.2 | 0.5 | 0.0 | X | Uncertain | Leu200, a hydrophobic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another hydrophobic residue, phenylalanine. Both the phenyl group of Phe200 and the branched iso-butyl hydrocarbon sidechain of Leu200 occupy an inward hydrophobic niche (e.g., Leu246, Val222, Phe231) during the simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||||||||
| c.601G>A | D201N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The remaining tools—Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is unavailable because two of the four inputs are uncertain. Foldetta also yields an uncertain result and is unavailable. Overall, the preponderance of evidence points to a benign impact for D201N, 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. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.686 | In-Between | 0.525 | Ambiguous | Likely Benign | 0.31 | Likely Benign | 0.0 | 1.21 | Ambiguous | 0.76 | Ambiguous | -0.10 | Likely Benign | 0.160 | Likely Benign | -2.36 | Neutral | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.08 | Benign | 0.13 | Tolerated | 0.0911 | 0.5413 | 2 | 1 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.602A>C | D201A 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 D201A variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. Uncertain or unavailable results come from Rosetta, Foldetta, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic, and Foldetta remains inconclusive. Overall, the majority of standard tools favor a benign classification, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s impact uncertain. The predictions do not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.793 | In-Between | 0.769 | Likely Pathogenic | Likely Benign | 0.45 | Likely Benign | 0.1 | 1.86 | Ambiguous | 1.16 | Ambiguous | 0.23 | Likely Benign | 0.261 | Likely Benign | -3.81 | Deleterious | 0.989 | Probably Damaging | 0.828 | Possibly Damaging | 4.11 | Benign | 0.09 | Tolerated | 0.3177 | 0.5050 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||
| c.602A>G | D201G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201G missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic interpretation, with no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | -7.744 | In-Between | 0.603 | Likely Pathogenic | Likely Benign | 0.71 | Ambiguous | 0.0 | 2.64 | Destabilizing | 1.68 | Ambiguous | 0.24 | Likely Benign | 0.289 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.877 | Possibly Damaging | 4.09 | Benign | 0.39 | Tolerated | 0.3268 | 0.5047 | 1 | -1 | 3.1 | -58.04 | ||||||||||||||||||||||||||||||
| c.603T>A | D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (ClinVar ID 3004688.0) is classified as **Benign** in ClinVar and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta, Foldetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as **Benign**, the SGM‑Consensus as **Likely Benign**, and Foldetta as **Uncertain**. Taken together, the overwhelming majority of evidence points to a benign impact, and this conclusion aligns with the ClinVar designation. Thus, the variant is most likely benign, with no contradiction to its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | Benign | 1 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | 0.165 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 0.1069 | 0.5505 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||||||
| c.603T>G | D201E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D201E missense variant (gnomAD ID 6‑33435245‑T‑G) is listed in ClinVar with an uncertain significance. Across a broad panel of in silico predictors, the majority indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all score benign. Only polyPhen‑2 HumDiv predicts pathogenicity, while Rosetta, Foldetta, and AlphaMissense‑Default remain inconclusive. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “likely benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta is inconclusive. Taken together, the preponderance of evidence points to a benign impact, which does not conflict with the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.366687 | Structured | 0.428570 | Uncertain | 0.698 | 0.447 | 0.125 | Conflicting | 2 | 6-33435245-T-G | 20 | 1.24e-5 | -2.640 | Likely Benign | 0.406 | Ambiguous | Likely Benign | 0.42 | Likely Benign | 0.2 | 1.99 | Ambiguous | 1.21 | Ambiguous | 0.23 | Likely Benign | 0.165 | Likely Benign | -0.69 | Neutral | 0.633 | Possibly Damaging | 0.108 | Benign | 4.30 | Benign | 1.00 | Tolerated | 3.46 | 9 | 0.1069 | 0.5505 | 3 | 2 | 0.0 | 14.03 | 258.7 | -24.8 | 0.9 | 0.1 | -0.3 | 0.2 | X | Uncertain | Asp201, an acidic residue located in the N-terminal loop before the first anti-parallel β sheet strand (res. Ile205-Pro208), is replaced by another acidic residue, glutamate. The carboxylate groups of both Asp201 and Glu201 side chains form hydrogen bonds with the hydroxyl group of Ser221 in the simulations. Due to its shorter side chain, Asp201 can also hydrogen bond with the backbone amide groups of neighboring loop residues Ser204 and Asp203. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.605A>G | E202G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E202G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Tools with uncertain or inconclusive results are Rosetta, AlphaMissense‑Default, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) leans toward pathogenic (2 pathogenic, 1 benign, 1 uncertain). Foldetta remains uncertain. Overall, the majority of standard prediction tools suggest a benign effect, and this conclusion does not contradict the lack of ClinVar reporting. Thus, the variant is most likely benign based on the current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.363090 | Structured | 0.429450 | Uncertain | 0.712 | 0.415 | 0.125 | -8.310 | Likely Pathogenic | 0.495 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.56 | Ambiguous | 0.27 | Likely Benign | 0.259 | Likely Benign | -4.70 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.01 | Benign | 0.07 | Tolerated | 0.3061 | 0.5405 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.607G>A | D203N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D203N is reported in gnomAD (variant ID 6-33435249‑G‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar; ESM1b is uncertain. The high‑accuracy consensus methods give a consistent benign signal: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction or folding stability result is missing or inconclusive. Based on the aggregate 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 | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | 6-33435249-G-A | 1 | 6.20e-7 | -7.465 | In-Between | 0.159 | Likely Benign | Likely Benign | -0.19 | Likely Benign | 0.1 | -0.12 | Likely Benign | -0.16 | Likely Benign | -0.03 | Likely Benign | 0.121 | Likely Benign | -2.26 | Neutral | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 4.06 | Benign | 0.06 | Tolerated | 3.44 | 10 | 0.0800 | 0.4296 | 1 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||
| c.608A>C | D203A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar; AlphaMissense‑Default 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 benign. All available predictions and stability analyses point to a benign impact. Therefore, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -6.807 | Likely Benign | 0.373 | Ambiguous | Likely Benign | 0.07 | Likely Benign | 0.1 | 0.49 | Likely Benign | 0.28 | Likely Benign | 0.12 | Likely Benign | 0.174 | Likely Benign | -3.34 | Deleterious | 0.941 | Possibly Damaging | 0.607 | Possibly Damaging | 4.05 | Benign | 0.17 | Tolerated | 0.2527 | 0.4128 | 0 | -2 | 5.3 | -44.01 | ||||||||||||||||||||||||||||||
| c.609T>A | D203E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203E 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 SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two PolyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly classify the variant as benign. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the majority of tools and the unanimous high‑accuracy 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 | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -4.067 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.08 | Likely Benign | 0.09 | Likely Benign | -0.07 | Likely Benign | 0.152 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 4.15 | Benign | 0.81 | Tolerated | 0.0975 | 0.4189 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.609T>G | D203E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D203E 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 SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two PolyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta (combining FoldX‑MD and Rosetta)—all uniformly classify the variant as benign. No prediction or folding‑stability result is missing or inconclusive. Based on the consensus of the majority of tools and the unanimous high‑accuracy 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 | PH | 0.314870 | Structured | 0.427620 | Uncertain | 0.740 | 0.407 | 0.125 | -4.067 | Likely Benign | 0.201 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.08 | Likely Benign | 0.09 | Likely Benign | -0.07 | Likely Benign | 0.152 | Likely Benign | -0.93 | Neutral | 0.990 | Probably Damaging | 0.675 | Possibly Damaging | 4.15 | Benign | 0.81 | Tolerated | 0.0975 | 0.4189 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.610T>A | S204T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic effect. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive, providing no definitive evidence. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of reliable predictors classify S204T as benign, and this conclusion does not contradict the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -4.164 | Likely Benign | 0.167 | Likely Benign | Likely Benign | 0.75 | Ambiguous | 0.1 | 1.19 | Ambiguous | 0.97 | Ambiguous | -0.52 | Ambiguous | 0.104 | Likely Benign | 0.55 | Neutral | 0.462 | Possibly Damaging | 0.173 | Benign | 4.19 | Benign | 1.00 | Tolerated | 0.0857 | 0.5063 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.610T>C | S204P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S204P variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and polyPhen‑2 HumVar, whereas a separate group predicts a pathogenic effect: FoldX, Rosetta, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. The remaining tools (premPS) are inconclusive and are not counted in either group. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain (treated as unavailable), the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie and therefore unavailable, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the majority of consensus predictions lean toward pathogenicity, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -8.855 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 3.71 | Destabilizing | 0.4 | 4.61 | Destabilizing | 4.16 | Destabilizing | 0.61 | Ambiguous | 0.137 | Likely Benign | -1.28 | Neutral | 0.808 | Possibly Damaging | 0.382 | Benign | 4.13 | Benign | 0.12 | Tolerated | 0.1430 | 0.4815 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.610T>G | S204A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S204A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from Rosetta, Foldetta, and premPS, which are treated as unavailable evidence. 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 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 | PH | 0.268042 | Structured | 0.420667 | Uncertain | 0.816 | 0.405 | 0.125 | -3.330 | Likely Benign | 0.084 | Likely Benign | Likely Benign | -0.09 | Likely Benign | 0.0 | -1.17 | Ambiguous | -0.63 | Ambiguous | -0.83 | Ambiguous | 0.091 | Likely Benign | 0.65 | Neutral | 0.004 | Benign | 0.004 | Benign | 4.28 | Benign | 0.27 | Tolerated | 0.3706 | 0.3495 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.613A>C | I205L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No contradictory evidence exists. Based on the collective predictions, the variant is most likely benign, 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 Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -5.474 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.07 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.05 | Likely Benign | 0.30 | Likely Benign | 0.112 | Likely Benign | -0.86 | Neutral | 0.004 | Benign | 0.012 | Benign | 4.17 | Benign | 0.34 | Tolerated | 0.0682 | 0.2702 | 2 | 2 | -0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.613A>G | I205V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205V is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the consensus of all available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -2.232 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.0 | -0.18 | Likely Benign | 0.14 | Likely Benign | 0.11 | Likely Benign | 0.113 | Likely Benign | -0.11 | Neutral | 0.001 | Benign | 0.007 | Benign | 4.20 | Benign | 0.84 | Tolerated | 0.0897 | 0.2791 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.613A>T | I205F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I205F missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, FATHMM, and polyPhen‑2 HumVar all classify it as benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome. Uncertain results from Foldetta, premPS, ESM1b, and Rosetta are treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta remains uncertain. Overall, the consensus of the majority of tools indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -7.913 | In-Between | 0.271 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.3 | 0.89 | Ambiguous | 0.60 | Ambiguous | 0.52 | Ambiguous | 0.113 | Likely Benign | -1.80 | Neutral | 0.838 | Possibly Damaging | 0.368 | Benign | 4.08 | Benign | 0.10 | Tolerated | 0.0461 | 0.2205 | 1 | 0 | -1.7 | 34.02 | |||||||||||||||||||||||||||||
| c.614T>A | I205N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I205N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. No evidence from these tools contradicts the lack of ClinVar annotation. Overall, the majority of predictions (five pathogenic vs. four benign) and the pathogenic SGM Consensus suggest the variant is most likely pathogenic, with no ClinVar status to conflict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -10.928 | Likely Pathogenic | 0.552 | Ambiguous | Likely Benign | 0.66 | Ambiguous | 0.1 | 1.16 | Ambiguous | 0.91 | Ambiguous | 1.57 | Destabilizing | 0.138 | Likely Benign | -3.56 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 4.06 | Benign | 0.07 | Tolerated | 0.0802 | 0.0212 | -2 | -3 | -8.0 | 0.94 | ||||||||||||||||||||||||||||||
| c.614T>C | I205T 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the remaining predictions (FoldX, premPS, AlphaMissense‑Default) are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Taken together, the consensus of both general and high‑accuracy predictors indicates that I205T 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 | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -6.869 | Likely Benign | 0.450 | Ambiguous | Likely Benign | 0.65 | Ambiguous | 0.0 | 0.28 | Likely Benign | 0.47 | Likely Benign | 0.81 | Ambiguous | 0.118 | Likely Benign | -2.19 | Neutral | 0.421 | Benign | 0.156 | Benign | 4.16 | Benign | 0.15 | Tolerated | 0.0933 | 0.0541 | 0 | -1 | -5.2 | -12.05 | |||||||||||||||||||||||||||||
| c.614T>G | I205S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 I205S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and ESM1b. Tools with uncertain or inconclusive results (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) 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 available predictions lean toward a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -8.694 | Likely Pathogenic | 0.518 | Ambiguous | Likely Benign | 1.17 | Ambiguous | 0.2 | 0.95 | Ambiguous | 1.06 | Ambiguous | 0.88 | Ambiguous | 0.178 | Likely Benign | -2.73 | Deleterious | 0.838 | Possibly Damaging | 0.368 | Benign | 4.12 | Benign | 0.24 | Tolerated | 0.2346 | 0.0800 | -1 | -2 | -5.3 | -26.08 | ||||||||||||||||||||||||||||||
| c.615T>G | I205M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I205M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as benign. Based on the majority of predictions and the high‑accuracy tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.264545 | Structured | 0.409933 | Uncertain | 0.821 | 0.414 | 0.125 | -6.693 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.2 | 0.63 | Ambiguous | 0.42 | Likely Benign | 0.65 | Ambiguous | 0.119 | Likely Benign | -1.16 | Neutral | 0.838 | Possibly Damaging | 0.467 | Possibly Damaging | 4.07 | Benign | 0.07 | Tolerated | 0.0593 | 0.2000 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.616A>C | I206L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and Foldetta. Those that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. Uncertain or inconclusive results come from premPS, AlphaMissense‑Optimized, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta predicts a benign outcome. Overall, the majority of tools (seven benign vs two pathogenic) support a benign classification. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -9.488 | Likely Pathogenic | 0.790 | Likely Pathogenic | Ambiguous | 0.05 | Likely Benign | 0.1 | 0.75 | Ambiguous | 0.40 | Likely Benign | 0.78 | Ambiguous | 0.080 | Likely Benign | -1.72 | Neutral | 0.004 | Benign | 0.012 | Benign | 3.78 | Benign | 0.08 | Tolerated | 0.0632 | 0.3608 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.616A>G | I206V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I206V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive results are from FoldX (uncertain) and Foldetta (uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.298791 | Structured | 0.405123 | Uncertain | 0.863 | 0.391 | 0.125 | -5.709 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 1.22 | Ambiguous | 0.1 | 0.24 | Likely Benign | 0.73 | Ambiguous | 0.40 | Likely Benign | 0.051 | Likely Benign | -0.51 | Neutral | 0.001 | Benign | 0.007 | Benign | 4.27 | Benign | 0.53 | Tolerated | 0.0833 | 0.2920 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.619A>C | K207Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K207Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, SIFT, and FATHMM; pathogenic predictions from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments give a mixed picture: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; AlphaMissense‑Optimized is uncertain; Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign impact. Folding‑stability scores from FoldX and Rosetta are inconclusive, and premPS is unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -9.544 | Likely Pathogenic | 0.874 | Likely Pathogenic | Ambiguous | 0.57 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.00 | Likely Benign | 0.61 | Ambiguous | 0.250 | Likely Benign | -2.95 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 4.00 | Benign | 0.10 | Tolerated | 0.4010 | 0.1797 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.619A>G | K207E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K207E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a larger group predicts pathogenicity: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic, the SGM Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. The remaining stability predictions (FoldX and Rosetta) are uncertain. Overall, the majority of evidence points to a pathogenic effect for K207E, 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 | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -14.387 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 1.39 | Ambiguous | 0.1 | 1.21 | Ambiguous | 1.30 | Ambiguous | 1.09 | Destabilizing | 0.265 | Likely Benign | -3.00 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 4.02 | Benign | 0.07 | Tolerated | 0.3504 | 0.1557 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.620A>C | K207T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K207T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain predictions come from 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 also pathogenic; Foldetta’s stability analysis is inconclusive. Overall, the preponderance of evidence points to a pathogenic effect for K207T, 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 | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -11.002 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | 2.15 | Destabilizing | 0.8 | 0.57 | Ambiguous | 1.36 | Ambiguous | 0.78 | Ambiguous | 0.239 | Likely Benign | -4.57 | Deleterious | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 3.99 | Benign | 0.07 | Tolerated | 0.1636 | 0.4031 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.620A>G | K207R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change K207R is not listed in ClinVar and has no reported allele in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign or likely benign outcome. In contrast, polyPhen‑2 HumDiv and HumVar classify the variant as pathogenic. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, providing no definitive support for either outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Taken together, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -5.157 | Likely Benign | 0.217 | Likely Benign | Likely Benign | -0.58 | Ambiguous | 0.1 | -1.07 | Ambiguous | -0.83 | Ambiguous | 0.37 | Likely Benign | 0.140 | Likely Benign | -1.77 | Neutral | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 4.09 | Benign | 0.20 | Tolerated | 0.4640 | 0.1704 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.621G>C | K207N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K207N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicating likely pathogenic, while Foldetta’s stability prediction is unavailable. Overall, the preponderance of evidence points to a pathogenic effect for K207N, 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 | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.881 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.123 | Likely Benign | -3.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.98 | Benign | 0.07 | Tolerated | 0.3184 | 0.2335 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.621G>T | K207N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K207N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and FATHMM, whereas pathogenic predictions arise from premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, and the SGM Consensus (majority vote) also predicts Pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. Overall, the preponderance of evidence indicates that K207N 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 | PH | 0.374039 | Structured | 0.406823 | Uncertain | 0.847 | 0.359 | 0.125 | -12.881 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.72 | Ambiguous | 0.1 | 1.48 | Ambiguous | 1.10 | Ambiguous | 1.00 | Destabilizing | 0.124 | Likely Benign | -3.54 | Deleterious | 0.995 | Probably Damaging | 0.829 | Possibly Damaging | 3.98 | Benign | 0.07 | Tolerated | 0.3184 | 0.2335 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.625G>C | V209L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V209L missense change is not reported in ClinVar and is absent from gnomAD. Consensus‐based predictors that agree on a benign outcome include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Predictors that flag a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -5.516 | Likely Benign | 0.837 | Likely Pathogenic | Ambiguous | 0.26 | Likely Benign | 0.4 | -0.12 | Likely Benign | 0.07 | Likely Benign | 0.08 | Likely Benign | 0.084 | Likely Benign | -0.96 | Neutral | 0.787 | Possibly Damaging | 0.259 | Benign | 4.08 | Benign | 0.39 | Tolerated | 0.0814 | 0.4188 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.625G>T | V209L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V209L is not reported in ClinVar and is absent from gnomAD. Consensus predictions from most in silico tools classify the change as benign: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and the SGM‑Consensus (Likely Benign). Only two tools predict a pathogenic effect: polyPhen‑2 HumDiv and AlphaMissense‑Default. The AlphaMissense‑Optimized score is uncertain. High‑accuracy assessments further support a benign outcome: the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.247041 | Structured | 0.397624 | Uncertain | 0.874 | 0.331 | 0.125 | -5.516 | Likely Benign | 0.837 | Likely Pathogenic | Ambiguous | 0.26 | Likely Benign | 0.4 | -0.12 | Likely Benign | 0.07 | Likely Benign | 0.08 | Likely Benign | 0.084 | Likely Benign | -0.96 | Neutral | 0.787 | Possibly Damaging | 0.259 | Benign | 4.08 | Benign | 0.39 | Tolerated | 0.0814 | 0.4188 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.631A>G | S211G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 HumDiv, and ESM1b; Rosetta is uncertain. High‑accuracy methods give a benign result for AlphaMissense‑Optimized and for Foldetta. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign vs two pathogenic). No evidence from ClinVar contradicts these predictions. Overall, the balance of evidence—including the unanimous benign calls from the high‑accuracy tools—suggests that the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.895 | Likely Pathogenic | 0.265 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.42 | Likely Benign | 1.07 | Destabilizing | 0.067 | Likely Benign | -3.17 | Deleterious | 0.787 | Possibly Damaging | 0.404 | Benign | 3.92 | Benign | 0.07 | Tolerated | 0.2560 | 0.4337 | 1 | 0 | 0.4 | -30.03 | ||||||||||||||||||||||||||||||
| c.632G>A | S211N 2D AIThe SynGAP1 S211N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, and FATHMM, whereas those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and premPS. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. 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 prediction leans toward pathogenicity, with no ClinVar entry to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -9.995 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | 0.60 | Ambiguous | 1.2 | 1.39 | Ambiguous | 1.00 | Ambiguous | 1.21 | Destabilizing | 0.174 | Likely Benign | -2.22 | Neutral | 0.982 | Probably Damaging | 0.747 | Possibly Damaging | 3.95 | Benign | 0.09 | Tolerated | 0.1534 | 0.4863 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.632G>C | S211T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S211T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools, FoldX and Rosetta, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign and Foldetta as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.209395 | Structured | 0.389893 | Uncertain | 0.846 | 0.300 | 0.125 | -10.301 | Likely Pathogenic | 0.678 | Likely Pathogenic | Likely Benign | 0.98 | Ambiguous | 0.5 | -0.78 | Ambiguous | 0.10 | Likely Benign | 0.50 | Likely Benign | 0.157 | Likely Benign | -2.33 | Neutral | 0.948 | Possibly Damaging | 0.484 | Possibly Damaging | 3.95 | Benign | 0.07 | Tolerated | 0.1678 | 0.5960 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.637A>C | I213L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM all classify the variant as benign, while AlphaMissense‑Default predicts it as pathogenic and ESM1b remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores the variant benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a benign effect. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the collective evidence, and this benign prediction does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -7.673 | In-Between | 0.577 | Likely Pathogenic | Likely Benign | 0.29 | Likely Benign | 0.4 | 0.20 | Likely Benign | 0.25 | Likely Benign | 0.45 | Likely Benign | 0.489 | Likely Benign | -1.45 | Neutral | 0.447 | Benign | 0.177 | Benign | 5.89 | Benign | 0.18 | Tolerated | 0.0771 | 0.2857 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.637A>G | I213V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I213V missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta’s stability analysis is uncertain. Overall, the evidence strongly favors a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.158265 | Structured | 0.372201 | Uncertain | 0.850 | 0.295 | 0.125 | -6.133 | Likely Benign | 0.364 | Ambiguous | Likely Benign | 0.67 | Ambiguous | 0.2 | 0.58 | Ambiguous | 0.63 | Ambiguous | 0.47 | Likely Benign | 0.413 | Likely Benign | -0.69 | Neutral | 0.128 | Benign | 0.048 | Benign | 5.82 | Benign | 0.10 | Tolerated | 0.1008 | 0.2959 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.646C>A | Q216K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216K 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, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of tools lean toward a benign classification, but the presence of several pathogenic predictions and a high‑accuracy consensus that is pathogenic introduces uncertainty. Thus, the variant is most likely benign, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.908 | Likely Pathogenic | 0.826 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | 0.38 | Likely Benign | 0.02 | Likely Benign | 0.17 | Likely Benign | 0.617 | Likely Pathogenic | -2.71 | Deleterious | 0.779 | Possibly Damaging | 0.351 | Benign | 5.92 | Benign | 0.12 | Tolerated | 0.2431 | 0.4591 | 1 | 1 | -0.4 | 0.04 | |||||||||||||||||||||||||||||
| c.646C>G | Q216E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -9.215 | Likely Pathogenic | 0.550 | Ambiguous | Likely Benign | 0.49 | Likely Benign | 0.3 | 0.30 | Likely Benign | 0.40 | Likely Benign | 0.35 | Likely Benign | 0.474 | Likely Benign | -1.89 | Neutral | 0.779 | Possibly Damaging | 0.351 | Benign | 5.85 | Benign | 0.13 | Tolerated | 0.1872 | 0.3117 | 2 | 2 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.647A>G | Q216R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant Q216R is not reported in ClinVar and has no gnomAD entry. Prediction tools that call the variant benign include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta as Benign. Overall, the predictions are split, with a slight edge toward pathogenicity. The variant is therefore most likely pathogenic based on the current computational evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.149 | Likely Pathogenic | 0.821 | Likely Pathogenic | Ambiguous | -0.42 | Likely Benign | 0.0 | 0.09 | Likely Benign | -0.17 | Likely Benign | -0.01 | Likely Benign | 0.513 | Likely Pathogenic | -2.70 | Deleterious | 0.963 | Probably Damaging | 0.549 | Possibly Damaging | 6.00 | Benign | 0.19 | Tolerated | 0.1972 | 0.2748 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.649G>A | E217K 2D 3DClick to see structure in 3D Viewer AISynGAP1 E217K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Computational predictions cluster into two groups: benign calls from premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM; pathogenic calls from REVEL, Rosetta, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. Three tools give uncertain results: FoldX, Foldetta, and ESM1b. High‑accuracy methods give conflicting outcomes: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; Foldetta remains uncertain. Because the majority of standard tools are split evenly and the high‑accuracy predictions are discordant, the evidence does not decisively support either outcome. The variant is therefore most likely pathogenic based on the preponderance of pathogenic predictions, 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. | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -7.169 | In-Between | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.52 | Ambiguous | 0.5 | 2.14 | Destabilizing | 1.33 | Ambiguous | 0.45 | Likely Benign | 0.563 | Likely Pathogenic | -2.38 | Neutral | 0.900 | Possibly Damaging | 0.307 | Benign | 5.95 | Benign | 0.13 | Tolerated | 0.2742 | 0.8216 | 0 | 1 | -0.4 | -0.94 | ||||||||||||||||||||||||||||||
| c.649G>C | E217Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E217Q is reported in gnomAD (ID 6‑33435291‑G‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With six benign versus three pathogenic calls and a benign consensus from the high‑accuracy panel, the variant is most likely benign. This conclusion does not contradict ClinVar, which contains no classification for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | 6-33435291-G-C | 1 | 6.20e-7 | -6.810 | Likely Benign | 0.949 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.2 | 1.61 | Ambiguous | 0.93 | Ambiguous | 0.67 | Ambiguous | 0.459 | Likely Benign | -1.89 | Neutral | 0.900 | Possibly Damaging | 0.461 | Possibly Damaging | 5.83 | Benign | 0.14 | Tolerated | 3.41 | 13 | 0.1474 | 0.8473 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||
| c.650A>C | E217A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217A 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, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. Four tools (FoldX, Rosetta, Foldetta, and ESM1b) returned uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; Foldetta’s stability prediction is uncertain. Overall, the majority of available predictions support a pathogenic impact for E217A. This conclusion is not contradicted by ClinVar status, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -7.294 | In-Between | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.67 | Ambiguous | 0.5 | 0.61 | Ambiguous | 0.64 | Ambiguous | 0.50 | Likely Benign | 0.619 | Likely Pathogenic | -3.88 | Deleterious | 0.900 | Possibly Damaging | 0.307 | Benign | 5.81 | Benign | 0.12 | Tolerated | 0.4442 | 0.8090 | 0 | -1 | 5.3 | -58.04 | ||||||||||||||||||||||||||||||
| c.650A>G | E217G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E217G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, SIFT, and FATHMM, while those that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized predicts a pathogenic impact, the SGM‑Consensus also indicates a likely pathogenic outcome, and Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic effect for E217G, 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 | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -8.076 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 1.13 | Ambiguous | 0.4 | 1.87 | Ambiguous | 1.50 | Ambiguous | 0.59 | Ambiguous | 0.684 | Likely Pathogenic | -3.93 | Deleterious | 0.816 | Possibly Damaging | 0.307 | Benign | 5.82 | Benign | 0.06 | Tolerated | 0.3278 | 0.6941 | 0 | -2 | 3.1 | -72.06 | |||||||||||||||||||||||||||||
| c.651G>C | E217D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E217D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the change as benign. The only inconclusive result comes from AlphaMissense‑Default, which is listed as uncertain. High‑accuracy assessments corroborate this benign profile: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports a benign outcome. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | -2.268 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.24 | Likely Benign | 0.3 | -0.07 | Likely Benign | 0.09 | Likely Benign | -0.34 | Likely Benign | 0.276 | Likely Benign | 0.66 | Neutral | 0.014 | Benign | 0.007 | Benign | 5.85 | Benign | 0.85 | Tolerated | 3.41 | 13 | 0.2066 | 0.5976 | 2 | 3 | 0.0 | -14.03 | |||||||||||||||||||||||||||
| c.651G>T | E217D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E217D is present in gnomAD (6‑33435293‑G‑T) but has no ClinVar entry. Functional prediction tools uniformly classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and Foldetta all report benign or benign‑like outcomes. No tool predicts pathogenicity. The high‑accuracy consensus methods corroborate this: AlphaMissense‑Optimized indicates benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports benign. AlphaMissense‑Default remains uncertain and is treated as unavailable. Overall, the evidence strongly supports a benign effect for E217D, 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 | PH | 0.278302 | Structured | 0.404912 | Uncertain | 0.823 | 0.284 | 0.000 | 6-33435293-G-T | 1 | 6.20e-7 | -2.268 | Likely Benign | 0.453 | Ambiguous | Likely Benign | 0.24 | Likely Benign | 0.3 | -0.07 | Likely Benign | 0.09 | Likely Benign | -0.34 | Likely Benign | 0.276 | Likely Benign | 0.66 | Neutral | 0.014 | Benign | 0.007 | Benign | 5.85 | Benign | 0.85 | Tolerated | 3.41 | 13 | 0.2066 | 0.5976 | 2 | 3 | 0.0 | -14.03 | ||||||||||||||||||||||||
| c.652T>A | F218I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218I is reported in gnomAD (variant ID 6‑33435294‑T‑A) but has no ClinVar entry. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized, while benign predictions are limited to polyPhen‑2 (HumVar), SIFT, and FATHMM. 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. 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 | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | 6-33435294-T-A | 1 | 6.20e-7 | -12.211 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 4.69 | Destabilizing | 0.2 | 5.93 | Destabilizing | 5.31 | Destabilizing | 1.18 | Destabilizing | 0.612 | Likely Pathogenic | -3.81 | Deleterious | 0.510 | Possibly Damaging | 0.066 | Benign | 5.85 | Benign | 0.08 | Tolerated | 3.41 | 13 | 0.2106 | 0.2459 | 0 | 1 | 1.7 | -34.02 | ||||||||||||||||||||||||
| c.652T>C | F218L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect comprise REVEL, Rosetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta provide uncertain results and are therefore considered unavailable for interpretation. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for F218L, 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 | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.861 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.4 | 2.36 | Destabilizing | 1.66 | Ambiguous | 1.08 | Destabilizing | 0.546 | Likely Pathogenic | -3.80 | Deleterious | 0.158 | Benign | 0.025 | Benign | 5.90 | Benign | 0.15 | Tolerated | 0.2331 | 0.3241 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.652T>G | F218V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; pathogenic predictions arise from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Pathogenic.” High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus agrees on a likely pathogenic outcome, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates pathogenicity. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion aligns with the absence of a ClinVar benign classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -10.081 | Likely Pathogenic | 0.978 | Likely Pathogenic | Likely Pathogenic | 4.18 | Destabilizing | 0.2 | 6.35 | Destabilizing | 5.27 | Destabilizing | 1.15 | Destabilizing | 0.691 | Likely Pathogenic | -4.14 | Deleterious | 0.300 | Benign | 0.066 | Benign | 5.81 | Benign | 0.08 | Tolerated | 0.2173 | 0.2258 | -1 | -1 | 1.4 | -48.04 | |||||||||||||||||||||||||||||
| c.653T>A | F218Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate a benign effect. The high‑accuracy folding‑stability tool Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts a benign impact. No tool predicts pathogenicity, and no contradictory evidence exists in ClinVar. **Based on the consensus of all predictions, the variant is most likely benign, and this assessment does not conflict with ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -3.596 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.26 | Likely Benign | 0.1 | -0.40 | Likely Benign | -0.07 | Likely Benign | -0.44 | Likely Benign | 0.229 | Likely Benign | 0.63 | Neutral | 0.001 | Benign | 0.002 | Benign | 5.95 | Benign | 0.52 | Tolerated | 0.1532 | 0.2725 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.653T>C | F218S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218S has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, SIFT, and FATHMM, whereas the remaining tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Based on the 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 | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.882 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 2.35 | Destabilizing | 0.1 | 3.00 | Destabilizing | 2.68 | Destabilizing | 1.22 | Destabilizing | 0.731 | Likely Pathogenic | -4.62 | Deleterious | 0.808 | Possibly Damaging | 0.225 | Benign | 5.80 | Benign | 0.07 | Tolerated | 0.3802 | 0.0454 | -3 | -2 | -3.6 | -60.10 | |||||||||||||||||||||||||||||
| c.654C>A | F218L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), Rosetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta are inconclusive and are treated as unavailable. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts Likely Pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.861 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.4 | 2.36 | Destabilizing | 1.66 | Ambiguous | 1.08 | Destabilizing | 0.477 | Likely Benign | -3.80 | Deleterious | 0.158 | Benign | 0.025 | Benign | 5.90 | Benign | 0.15 | Tolerated | 0.2331 | 0.3241 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.654C>G | F218L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F218L is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), Rosetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Foldetta are inconclusive and are treated as unavailable. High‑accuracy methods further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts Likely Pathogenic; Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact. There is no ClinVar annotation to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.281712 | Structured | 0.408725 | Uncertain | 0.848 | 0.272 | 0.000 | -8.861 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.96 | Ambiguous | 0.4 | 2.36 | Destabilizing | 1.66 | Ambiguous | 1.08 | Destabilizing | 0.477 | Likely Benign | -3.80 | Deleterious | 0.158 | Benign | 0.025 | Benign | 5.90 | Benign | 0.15 | Tolerated | 0.2331 | 0.3241 | 2 | 0 | 1.0 | -34.02 | |||||||||||||||||||||||||||||
| c.661G>C | E221Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E221Q missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Two tools predict a pathogenic outcome: ESM1b and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (two pathogenic vs two benign), and Foldetta predicts a benign effect. Overall, the majority of evidence (10 benign vs 2 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.127496 | Structured | 0.413334 | Uncertain | 0.891 | 0.283 | 0.000 | -8.243 | Likely Pathogenic | 0.825 | Likely Pathogenic | Ambiguous | -0.26 | Likely Benign | 0.1 | -0.33 | Likely Benign | -0.30 | Likely Benign | 0.12 | Likely Benign | 0.455 | Likely Benign | -1.64 | Neutral | 0.028 | Benign | 0.015 | Benign | 6.13 | Benign | 0.23 | Tolerated | 0.1207 | 0.7690 | 2 | 2 | 0.0 | -0.98 | ||||||||||||||||||||||||||||||
| c.664G>A | V222I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 V222I 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, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The high‑accuracy consensus methods give a benign signal: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, while Foldetta’s stability assessment is uncertain. Overall, the majority of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -6.347 | Likely Benign | 0.604 | Likely Pathogenic | Likely Benign | 0.21 | Likely Benign | 0.2 | 1.45 | Ambiguous | 0.83 | Ambiguous | 0.09 | Likely Benign | 0.612 | Likely Pathogenic | -0.87 | Neutral | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.77 | Benign | 0.08 | Tolerated | 0.0637 | 0.3574 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.667A>G | T223A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223A is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33435518‑A‑G). Functional prediction tools that agree on a benign effect include FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and PROVEAN. Predictions that are inconclusive are Rosetta, Foldetta, premPS, and ESM1b. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also resolves to benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. 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. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | Uncertain | 1 | 6-33435518-A-G | 3 | 1.86e-6 | -7.076 | In-Between | 0.316 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.1 | 0.77 | Ambiguous | 0.54 | Ambiguous | 0.74 | Ambiguous | 0.574 | Likely Pathogenic | -3.36 | Deleterious | 0.231 | Benign | 0.058 | Benign | 5.74 | Benign | 0.09 | Tolerated | 3.41 | 13 | 0.2982 | 0.3031 | 1 | 0 | 2.5 | -30.03 | 186.4 | 44.0 | 0.0 | 0.0 | 0.0 | 0.0 | X | X | Uncertain | The introduced residue Ala223 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr223 side chain in the WT protein, the methyl side chain of Ala223 cannot form hydrogen bonds with nearby residues Thr228 and Lys207. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and partially unfolds in the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.668C>G | T223R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T223R has no ClinVar entry and is not reported in gnomAD. Functional prediction tools show a mixed profile: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, and FATHMM, while pathogenic calls arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy consensus (SGM Consensus) favors pathogenicity (3/4 votes pathogenic), whereas Foldetta predicts benign stability. Because the majority of individual predictors lean benign and the high‑accuracy consensus is split, the overall assessment remains inconclusive. The variant is most likely benign, but the presence of several pathogenic predictions and the SGM Consensus result indicates that pathogenicity cannot be ruled out. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -12.079 | Likely Pathogenic | 0.794 | Likely Pathogenic | Ambiguous | -0.36 | Likely Benign | 0.1 | -0.27 | Likely Benign | -0.32 | Likely Benign | 0.75 | Ambiguous | 0.827 | Likely Pathogenic | -4.62 | Deleterious | 0.561 | Possibly Damaging | 0.178 | Benign | 5.73 | Benign | 0.06 | Tolerated | 0.0708 | 0.2407 | -1 | -1 | -3.8 | 55.08 | |||||||||||||||||||||||||||||
| c.668C>T | T223I 2D  AIThe SynGAP1 T223I variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that clearly indicate benign impact include FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict pathogenicity are REVEL and PROVEAN. Predictions that are inconclusive (Rosetta, Foldetta, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of definitive predictions support a benign effect. Thus, the variant is 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. | PH | 0.070400 | Structured | 0.382605 | Uncertain | 0.867 | 0.316 | 0.125 | -6.543 | Likely Benign | 0.356 | Ambiguous | Likely Benign | -0.24 | Likely Benign | 0.8 | -0.99 | Ambiguous | -0.62 | Ambiguous | 0.30 | Likely Benign | 0.640 | Likely Pathogenic | -4.09 | Deleterious | 0.010 | Benign | 0.005 | Benign | 5.93 | Benign | 0.07 | Tolerated | 0.0569 | 0.5393 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||
| c.670A>C | T224P 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T224P 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 are SIFT and FATHMM, while the remaining tools (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b) all predict a pathogenic impact; premPS is uncertain. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, 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 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 | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -11.812 | Likely Pathogenic | 0.960 | Likely Pathogenic | Likely Pathogenic | 3.63 | Destabilizing | 0.4 | 2.68 | Destabilizing | 3.16 | Destabilizing | 0.57 | Ambiguous | 0.765 | Likely Pathogenic | -3.65 | Deleterious | 0.971 | Probably Damaging | 0.543 | Possibly Damaging | 5.56 | Benign | 0.23 | Tolerated | 0.2355 | 0.6063 | 0 | -1 | -0.9 | -3.99 | |||||||||||||||||||||||||||||
| c.670A>G | T224A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T224A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33435521‑A‑G). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and AlphaMissense‑Default. The remaining tools (Rosetta, Foldetta, premPS, ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | Uncertain | 3 | 6-33435521-A-G | 2 | 1.24e-6 | -7.379 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | 0.33 | Likely Benign | 0.1 | 1.05 | Ambiguous | 0.69 | Ambiguous | 0.91 | Ambiguous | 0.464 | Likely Benign | -2.96 | Deleterious | 0.243 | Benign | 0.079 | Benign | 5.57 | Benign | 0.57 | Tolerated | 3.41 | 13 | 0.4253 | 0.5053 | 1 | 0 | 2.5 | -30.03 | 169.0 | 41.4 | -0.5 | 1.1 | -0.4 | 0.0 | X | X | Uncertain | The introduced residue Ala224 is located on the outer surface of an anti-parallel β sheet strand (res. Cys219-Thr224). Unlike the hydroxyl group of the Thr224 side chain in the WT model, the methyl side chain of Ala224 cannot form hydrogen bonds with nearby residues Ser204, Ser226, and Gly227. Without these hydrogen-bonding interactions at the β sheet surface, the secondary structure element becomes unstable and unfolds during the variant simulations. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | |||||||||||||
| c.670A>T | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | 0.412 | Likely Benign | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 0.3498 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.671C>A | T224N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224N missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are premPS, polyPhen‑2 HumDiv, and AlphaMissense‑Default. Uncertain or inconclusive results come from FoldX, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, indicating no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -7.342 | In-Between | 0.814 | Likely Pathogenic | Ambiguous | 0.66 | Ambiguous | 0.2 | -0.06 | Likely Benign | 0.30 | Likely Benign | 1.15 | Destabilizing | 0.370 | Likely Benign | -2.40 | Neutral | 0.845 | Possibly Damaging | 0.368 | Benign | 5.54 | Benign | 0.34 | Tolerated | 0.1460 | 0.5079 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||
| c.671C>G | T224S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224S missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only polyPhen‑2 (HumDiv) predicts a pathogenic outcome; the remaining tools (Foldetta, premPS, AlphaMissense‑Default, Rosetta) give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -5.928 | Likely Benign | 0.558 | Ambiguous | Likely Benign | 0.29 | Likely Benign | 0.1 | 0.70 | Ambiguous | 0.50 | Ambiguous | 0.71 | Ambiguous | 0.374 | Likely Benign | -2.09 | Neutral | 0.608 | Possibly Damaging | 0.079 | Benign | 5.56 | Benign | 0.66 | Tolerated | 0.3498 | 0.4994 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.671C>T | T224I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T224I 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, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. With an equal split of benign and pathogenic calls overall, the two high‑accuracy pathogenic predictions outweigh the single high‑accuracy benign prediction, indicating that the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar assertion is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.360921 | Uncertain | 0.848 | 0.315 | 0.125 | -8.831 | Likely Pathogenic | 0.973 | Likely Pathogenic | Likely Pathogenic | 0.49 | Likely Benign | 0.2 | 0.35 | Likely Benign | 0.42 | Likely Benign | 0.02 | Likely Benign | 0.657 | Likely Pathogenic | -3.47 | Deleterious | 0.608 | Possibly Damaging | 0.154 | Benign | 5.58 | Benign | 0.38 | Tolerated | 0.1015 | 0.7225 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.673T>A | S225T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -6.351 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.64 | Ambiguous | 0.4 | 0.59 | Ambiguous | 0.62 | Ambiguous | 0.03 | Likely Benign | 0.244 | Likely Benign | -1.98 | Neutral | 0.118 | Benign | 0.049 | Benign | 5.73 | Benign | 0.55 | Tolerated | 0.1419 | 0.7395 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.673T>C | S225P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign calls come from premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, while pathogenic calls arise from REVEL, FoldX, PROVEAN, and ESM1b. Two tools—Rosetta and Foldetta—return uncertain results and are treated as unavailable. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts benign, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta remains unavailable. Overall, the majority of evidence leans toward a benign effect, and this conclusion does not conflict with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -8.084 | Likely Pathogenic | 0.156 | Likely Benign | Likely Benign | 2.22 | Destabilizing | 1.8 | 1.14 | Ambiguous | 1.68 | Ambiguous | 0.15 | Likely Benign | 0.503 | Likely Pathogenic | -3.31 | Deleterious | 0.396 | Benign | 0.133 | Benign | 5.91 | Benign | 0.17 | Tolerated | 0.2128 | 0.6946 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.673T>G | S225A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225A is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is inconclusive (uncertain) and therefore does not alter the overall benign assessment. Consequently, the variant is most likely benign based on the available predictions, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | -3.752 | Likely Benign | 0.052 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.3 | 0.79 | Ambiguous | 0.55 | Ambiguous | 0.11 | Likely Benign | 0.201 | Likely Benign | -1.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.79 | Benign | 0.58 | Tolerated | 0.4840 | 0.5897 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.674C>T | S225L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S225L is reported in gnomAD (6‑33435525‑C‑T) but has no ClinVar entry. In silico predictors that agree on a benign effect include REVEL, FoldX, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. Predictions that are inconclusive are Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign effect for S225L, 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 | PH | 0.150080 | Structured | 0.344191 | Uncertain | 0.817 | 0.319 | 0.250 | 6-33435525-C-T | 1 | 6.20e-7 | -6.644 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.29 | Likely Benign | 0.4 | 1.18 | Ambiguous | 0.74 | Ambiguous | 0.18 | Likely Benign | 0.320 | Likely Benign | -3.76 | Deleterious | 0.000 | Benign | 0.001 | Benign | 5.70 | Benign | 0.28 | Tolerated | 3.41 | 13 | 0.1039 | 0.6554 | -2 | -3 | 4.6 | 26.08 | ||||||||||||||||||||||||
| c.676T>G | S226A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Consequently, the variant is most likely benign based on current predictions, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -4.665 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.06 | Likely Benign | 0.0 | 0.25 | Likely Benign | 0.16 | Likely Benign | -0.02 | Likely Benign | 0.339 | Likely Benign | -1.64 | Neutral | 0.123 | Benign | 0.050 | Benign | 5.76 | Benign | 0.06 | Tolerated | 0.4812 | 0.5599 | 1 | 1 | 2.6 | -16.00 | |||||||||||||||||||||||||||||
| c.682A>T | T228S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T228S missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, and Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign stability change. Taken together, the overwhelming majority of evidence indicates a benign impact for T228S. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -2.028 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.63 | Ambiguous | 0.48 | Likely Benign | 0.05 | Likely Benign | 0.458 | Likely Benign | -0.50 | Neutral | 0.734 | Possibly Damaging | 0.138 | Benign | 5.65 | Benign | 1.00 | Tolerated | 0.3395 | 0.5107 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.683C>T | T228I 2D AIThe SynGAP1 missense variant T228I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With eight tools favoring pathogenicity versus six favoring benign, and two of the three high‑accuracy methods supporting pathogenicity, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which currently contains no entry for T228I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.104810 | Structured | 0.321733 | Uncertain | 0.829 | 0.316 | 0.125 | -8.605 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.02 | Likely Benign | 0.6 | 0.21 | Likely Benign | 0.12 | Likely Benign | 0.23 | Likely Benign | 0.692 | Likely Pathogenic | -3.99 | Deleterious | 0.984 | Probably Damaging | 0.690 | Possibly Damaging | 5.65 | Benign | 0.06 | Tolerated | 0.0951 | 0.7051 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.685A>G | K229E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K229E is not reported in ClinVar (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that classify the variant as benign include FoldX, Rosetta, premPS, SIFT, and FATHMM. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall distribution of predictions, the variant is most likely pathogenic; this conclusion does not contradict the ClinVar status, which currently has no entry for K229E. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | -12.828 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.0 | 0.24 | Likely Benign | 0.36 | Likely Benign | 0.18 | Likely Benign | 0.816 | Likely Pathogenic | -3.10 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.84 | Benign | 0.09 | Tolerated | 0.3915 | 0.0793 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.686A>G | K229R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K229R missense variant is catalogued in gnomAD (ID 6‑33435537‑A‑G) but has no entry in ClinVar. Functional prediction tools largely agree on a benign effect: FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict benign. In contrast, REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar predict pathogenic. AlphaMissense‑Default is uncertain and is treated as unavailable. The high‑accuracy consensus methods reinforce the benign assessment: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.179055 | Structured | 0.310912 | Uncertain | 0.843 | 0.306 | 0.000 | 6-33435537-A-G | 1 | 6.20e-7 | -5.651 | Likely Benign | 0.437 | Ambiguous | Likely Benign | 0.09 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.06 | Likely Benign | 0.40 | Likely Benign | 0.628 | Likely Pathogenic | -2.00 | Neutral | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.84 | Benign | 0.19 | Tolerated | 3.43 | 12 | 0.4921 | 0.0972 | 2 | 3 | -0.6 | 28.01 | ||||||||||||||||||||||||
| c.688T>A | C230S 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. With an equal split of 7 benign versus 7 pathogenic predictions overall, the higher‑confidence tools lean toward pathogenicity. Therefore, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -9.994 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.05 | Likely Benign | 0.24 | Likely Benign | 1.08 | Destabilizing | 0.859 | Likely Pathogenic | -8.24 | Deleterious | 0.421 | Benign | 0.115 | Benign | 5.91 | Benign | 0.07 | Tolerated | 0.4926 | 0.1822 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.689G>A | C230Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C230Y is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that indicate a benign effect include FoldX, Rosetta, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus score is “Likely Pathogenic,” and the Foldetta stability assessment is “Uncertain.” High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -8.978 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | -0.03 | Likely Benign | 0.1 | -2.24 | Stabilizing | -1.14 | Ambiguous | 0.00 | Likely Benign | 0.816 | Likely Pathogenic | -8.46 | Deleterious | 0.940 | Possibly Damaging | 0.641 | Possibly Damaging | 6.17 | Benign | 0.14 | Tolerated | 0.1159 | 0.3655 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.689G>C | C230S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant C230S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools cluster into two groups: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM; pathogenic calls come from REVEL, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as benign. No prediction or stability result is missing. Overall, the predictions are evenly split between benign and pathogenic, leaving the variant’s functional impact uncertain. This uncertainty does not contradict ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.268042 | Structured | 0.308076 | Uncertain | 0.870 | 0.308 | 0.000 | -9.994 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.42 | Likely Benign | 0.1 | 0.05 | Likely Benign | 0.24 | Likely Benign | 1.08 | Destabilizing | 0.844 | Likely Pathogenic | -8.24 | Deleterious | 0.421 | Benign | 0.115 | Benign | 5.91 | Benign | 0.07 | Tolerated | 0.4926 | 0.1822 | 0 | -1 | -3.3 | -16.06 | |||||||||||||||||||||||||||||
| c.692T>A | F231Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant F231Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on benign effects include Rosetta, Foldetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict pathogenicity are REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; FoldX and premPS are inconclusive. High‑accuracy methods give AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of standard tools lean benign, but the two most accurate predictors and the consensus vote favor pathogenicity. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no classification for F231Y. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.366687 | Structured | 0.306467 | Uncertain | 0.895 | 0.300 | 0.000 | -9.831 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 0.69 | Ambiguous | 0.1 | 0.00 | Likely Benign | 0.35 | Likely Benign | 0.85 | Ambiguous | 0.687 | Likely Pathogenic | -2.60 | Deleterious | 0.437 | Benign | 0.079 | Benign | 5.50 | Benign | 0.12 | Tolerated | 0.1355 | 0.2732 | 7 | 3 | -4.1 | 16.00 | |||||||||||||||||||||||||||||
| c.694G>A | A232T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232T is listed in ClinVar as Benign (ClinVar ID 1165963.0) and is present in gnomAD (ID 6‑33435545‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv and AlphaMissense‑Default. Predictions that are inconclusive are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports Benign. Overall, the majority of evidence supports a benign impact, which is consistent with the ClinVar classification and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | Benign | 1 | 6-33435545-G-A | 1 | 6.20e-7 | -7.655 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | 0.47 | Likely Benign | 0.1 | -0.04 | Likely Benign | 0.22 | Likely Benign | 0.61 | Ambiguous | 0.469 | Likely Benign | -1.42 | Neutral | 0.608 | Possibly Damaging | 0.240 | Benign | 5.80 | Benign | 0.09 | Tolerated | 3.40 | 14 | 0.1621 | 0.6488 | 1 | 0 | -2.5 | 30.03 | 210.8 | -42.0 | 0.5 | 0.1 | 0.4 | 0.5 | X | Uncertain | The hydroxyl group of Thr232, located at the end of an anti-parallel β sheet strand (res. Thr228-Ala232), forms hydrogen bonds with nearby residues Glu217, Cys233, and Cys219 in the variant simulations. These hydrogen-bonding interactions at the β sheet surface contribute to the stability of the secondary structure element and prevent it from unfolding. The new hydrogen bond interactions may be more favorable for structural stability than the steric interactions of the methyl side chain of Ala with the side chains of Gln216 and Cys219 in the WT. However, since the model ends abruptly at the N-terminus, no definite conclusions can be drawn from the simulations. | ||||||||||||||
| c.694G>C | A232P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and FATHMM. Tools that agree on a pathogenic effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain or inconclusive results come from Rosetta, premPS, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome, and Foldetta remains uncertain. Overall, the majority of evaluated tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -12.697 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.8 | 1.25 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | 0.748 | Likely Pathogenic | -2.75 | Deleterious | 0.917 | Possibly Damaging | 0.502 | Possibly Damaging | 5.78 | Benign | 0.06 | Tolerated | 0.2163 | 0.5259 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.694G>T | A232S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A232S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Across the evaluated in‑silico predictors, all tools except AlphaMissense‑Default converge on a benign interpretation: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all predict benign. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -3.264 | Likely Benign | 0.344 | Ambiguous | Likely Benign | 0.23 | Likely Benign | 0.1 | -0.23 | Likely Benign | 0.00 | Likely Benign | -0.20 | Likely Benign | 0.378 | Likely Benign | 0.54 | Neutral | 0.057 | Benign | 0.025 | Benign | 5.95 | Benign | 1.00 | Tolerated | 0.2777 | 0.5300 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.695C>G | A232G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A232G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the change as benign include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Those that predict pathogenicity are polyPhen‑2 HumDiv and AlphaMissense‑Default. Uncertain or inconclusive results come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence points to a benign effect; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | -4.924 | Likely Benign | 0.835 | Likely Pathogenic | Ambiguous | 0.43 | Likely Benign | 0.1 | 1.43 | Ambiguous | 0.93 | Ambiguous | 0.53 | Ambiguous | 0.453 | Likely Benign | -1.39 | Neutral | 0.608 | Possibly Damaging | 0.172 | Benign | 5.81 | Benign | 0.11 | Tolerated | 0.2012 | 0.4724 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.695C>T | A232V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A232V is catalogued in gnomAD (ID 6‑33435546‑C‑T) but has no ClinVar entry. Functional prediction tools show mixed results: benign calls come from FoldX, Rosetta, Foldetta, polyPhen‑2 HumVar, SIFT, and FATHMM, whereas pathogenic calls are reported by REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, and the Foldetta stability assessment predicts benign. premPS is inconclusive and therefore not considered. Overall, the majority of independent predictors lean toward pathogenicity, but the stability‑based Foldetta suggests a benign effect. With no ClinVar classification to contradict, the variant is most likely pathogenic according to the prevailing computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.254060 | Structured | 0.307228 | Uncertain | 0.878 | 0.305 | 0.000 | 6-33435546-C-T | 2 | 1.24e-6 | -9.418 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 0.23 | Likely Benign | 0.32 | Likely Benign | 0.55 | Ambiguous | 0.539 | Likely Pathogenic | -2.99 | Deleterious | 0.608 | Possibly Damaging | 0.240 | Benign | 5.85 | Benign | 0.06 | Tolerated | 3.40 | 14 | 0.1202 | 0.6027 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||
| c.697T>G | C233G 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C233G is not reported in ClinVar (ClinVar ID = None) and has no entry in gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include polyPhen‑2 HumVar, SIFT, and FATHMM. Tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta are inconclusive and are treated as unavailable. High‑accuracy predictions: AlphaMissense‑Optimized reports Pathogenic; SGM‑Consensus reports Likely Pathogenic; Foldetta is Uncertain. Overall, the majority of available predictions indicate a pathogenic impact. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.306787 | Uncertain | 0.868 | 0.322 | 0.000 | -14.155 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | 1.29 | Ambiguous | 0.1 | 1.01 | Ambiguous | 1.15 | Ambiguous | 1.31 | Destabilizing | 0.849 | Likely Pathogenic | -10.68 | Deleterious | 0.596 | Possibly Damaging | 0.107 | Benign | 5.79 | Benign | 0.09 | Tolerated | 0.3317 | 0.3570 | -3 | -3 | -2.9 | -46.09 | |||||||||||||||||||||||||||||
| c.700C>G | R234G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234G missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. Those that agree on a pathogenic effect are REVEL, PROVEAN, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of individual predictors lean toward pathogenicity, and the high‑accuracy consensus also supports a pathogenic classification. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -7.163 | In-Between | 0.923 | Likely Pathogenic | Ambiguous | 1.50 | Ambiguous | 0.2 | 0.88 | Ambiguous | 1.19 | Ambiguous | 0.61 | Ambiguous | 0.724 | Likely Pathogenic | -4.31 | Deleterious | 0.276 | Benign | 0.103 | Benign | 5.82 | Benign | 0.12 | Tolerated | 0.3194 | 0.3426 | -3 | -2 | 4.1 | -99.14 | ||||||||||||||||||||||||||||||
| c.701G>A | R234Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 R234Q missense variant is not reported in ClinVar (ClinVar ID = None) but is present in gnomAD (ID = 6‑33435552‑G‑A). Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are REVEL, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default; premPS is uncertain and treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence points to a benign effect. The variant’s predicted benign status does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | 6-33435552-G-A | 8 | 4.96e-6 | -9.675 | Likely Pathogenic | 0.666 | Likely Pathogenic | Likely Benign | 0.21 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.24 | Likely Benign | 0.57 | Ambiguous | 0.627 | Likely Pathogenic | -2.32 | Neutral | 0.892 | Possibly Damaging | 0.213 | Benign | 5.81 | Benign | 0.11 | Tolerated | 3.40 | 14 | 0.3256 | 0.2520 | 1 | 1 | 1.0 | -28.06 | |||||||||||||||||||||||||
| c.701G>T | R234L 2D AIThe SynGAP1 missense variant R234L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, polyPhen‑2 HumVar, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Four tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy methods show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of predictions (7 pathogenic vs. 4 benign) and the pathogenic consensus from the high‑accuracy SGM‑Consensus suggest that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.239899 | Structured | 0.311558 | Uncertain | 0.804 | 0.322 | 0.000 | -11.153 | Likely Pathogenic | 0.935 | Likely Pathogenic | Ambiguous | 1.38 | Ambiguous | 0.9 | 0.50 | Ambiguous | 0.94 | Ambiguous | 0.20 | Likely Benign | 0.734 | Likely Pathogenic | -4.64 | Deleterious | 0.649 | Possibly Damaging | 0.199 | Benign | 5.78 | Benign | 0.11 | Tolerated | 0.1846 | 0.4783 | -3 | -2 | 8.3 | -43.03 | |||||||||||||||||||||||||||||
| c.703T>A | S235T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, Rosetta, and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or folding result is missing or inconclusive. Based on the overall consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | -9.422 | Likely Pathogenic | 0.451 | Ambiguous | Likely Benign | 0.80 | Ambiguous | 0.0 | -0.54 | Ambiguous | 0.13 | Likely Benign | 0.21 | Likely Benign | 0.453 | Likely Benign | -2.02 | Neutral | 0.057 | Benign | 0.020 | Benign | 5.75 | Benign | 0.13 | Tolerated | 0.1674 | 0.6337 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.706G>C | A236P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A236P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized, whereas those that predict a pathogenic outcome are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and AlphaMissense‑Default; the remaining tools (FoldX, Rosetta, premPS, ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No prediction or stability result is missing or inconclusive. Overall, the majority of individual tools lean toward pathogenicity, but the two most reliable high‑accuracy methods (AlphaMissense‑Optimized and Foldetta) suggest a benign effect, while the SGM Consensus indicates pathogenicity. Given the mixed evidence, the variant is most likely benign based on the strongest high‑accuracy 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. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.932 | In-Between | 0.621 | Likely Pathogenic | Likely Benign | -0.99 | Ambiguous | 0.1 | 1.44 | Ambiguous | 0.23 | Likely Benign | 0.67 | Ambiguous | 0.862 | Likely Pathogenic | -4.31 | Deleterious | 0.995 | Probably Damaging | 0.880 | Possibly Damaging | 5.78 | Benign | 0.12 | Tolerated | 0.1980 | 0.4897 | 1 | -1 | -3.4 | 26.04 | ||||||||||||||||||||||||||||||
| c.706G>T | A236S 2D AIThe SynGAP1 A236S variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are inconclusive or uncertain are Rosetta, Foldetta, premPS, and ESM1b. 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, the SGM Consensus as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for A236S, 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 Benign | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.845 | In-Between | 0.106 | Likely Benign | Likely Benign | 0.40 | Likely Benign | 0.5 | 1.24 | Ambiguous | 0.82 | Ambiguous | 0.65 | Ambiguous | 0.648 | Likely Pathogenic | -2.30 | Neutral | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.83 | Benign | 0.13 | Tolerated | 0.2641 | 0.5547 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.707C>G | A236G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A236G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, premPS, and PROVEAN. Four tools (FoldX, Rosetta, Foldetta, and ESM1b) return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also favors benign, while Foldetta remains uncertain. Overall, the majority of available predictions support a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.185198 | Structured | 0.329926 | Uncertain | 0.775 | 0.330 | 0.000 | -7.412 | In-Between | 0.162 | Likely Benign | Likely Benign | 0.92 | Ambiguous | 0.1 | 1.15 | Ambiguous | 1.04 | Ambiguous | 1.09 | Destabilizing | 0.615 | Likely Pathogenic | -3.35 | Deleterious | 0.067 | Benign | 0.028 | Benign | 5.74 | Benign | 0.07 | Tolerated | 0.2200 | 0.3899 | 1 | 0 | -2.2 | -14.03 | ||||||||||||||||||||||||||||||
| c.709G>A | A237T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A237T missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 (HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv), and ESM1b. Four tools (FoldX, Rosetta, Foldetta, premPS) return uncertain results. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split; Foldetta also yields an inconclusive stability assessment. Overall, the majority of evidence leans toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.664 | Likely Pathogenic | 0.213 | Likely Benign | Likely Benign | 0.74 | Ambiguous | 0.3 | 0.55 | Ambiguous | 0.65 | Ambiguous | 0.71 | Ambiguous | 0.539 | Likely Pathogenic | -2.66 | Deleterious | 0.900 | Possibly Damaging | 0.348 | Benign | 5.80 | Benign | 0.06 | Tolerated | 0.0975 | 0.5737 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.709G>T | A237S 2D AIThe SynGAP1 missense variant A237S is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and FATHMM. No tool predicts a pathogenic outcome; the only inconclusive results come from premPS and ESM1b, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -7.696 | In-Between | 0.112 | Likely Benign | Likely Benign | 0.48 | Likely Benign | 0.6 | 0.34 | Likely Benign | 0.41 | Likely Benign | 0.61 | Ambiguous | 0.421 | Likely Benign | -1.41 | Neutral | 0.259 | Benign | 0.048 | Benign | 5.82 | Benign | 0.31 | Tolerated | 0.2209 | 0.4357 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.710C>T | A237V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A237V is not reported in ClinVar and is absent from gnomAD. Standard in‑silico predictors are divided: benign calls come from premPS, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic calls come from REVEL, PROVEAN, polyPhen‑2 HumDiv, and ESM1b. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, a pathogenic outcome from the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and an uncertain result from Foldetta. Because the majority of conventional predictors and the optimized AlphaMissense model favor benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.200174 | Structured | 0.334699 | Uncertain | 0.719 | 0.352 | 0.000 | -8.927 | Likely Pathogenic | 0.397 | Ambiguous | Likely Benign | 0.87 | Ambiguous | 0.4 | 0.97 | Ambiguous | 0.92 | Ambiguous | 0.18 | Likely Benign | 0.565 | Likely Pathogenic | -3.26 | Deleterious | 0.900 | Possibly Damaging | 0.430 | Benign | 5.87 | Benign | 0.10 | Tolerated | 0.0771 | 0.4853 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.712G>C | E238Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E238Q missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into two consensus groups: benign predictions come from SIFT and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods (FoldX, Rosetta, premPS) and Foldetta give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, while Foldetta remains uncertain. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.194234 | Structured | 0.332638 | Uncertain | 0.796 | 0.326 | 0.000 | -11.476 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 0.63 | Ambiguous | 0.5 | 0.59 | Ambiguous | 0.61 | Ambiguous | 0.52 | Ambiguous | 0.723 | Likely Pathogenic | -2.72 | Deleterious | 0.996 | Probably Damaging | 0.891 | Possibly Damaging | 5.44 | Benign | 0.06 | Tolerated | 0.1372 | 0.5412 | 2 | 2 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.720C>A | D240E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D240E missense variant is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, while those that agree on a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are 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 majority of evaluated predictors (seven pathogenic vs. four benign) lean toward a pathogenic interpretation. Thus, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -8.619 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.50 | Ambiguous | 0.28 | Likely Benign | 0.713 | Likely Pathogenic | -3.43 | Deleterious | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 5.84 | Benign | 0.10 | Tolerated | 0.1155 | 0.5066 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.720C>G | D240E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D240E is a missense change in the PH domain. No ClinVar entry exists for this variant, and it is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from SIFT, FoldX, premPS, and FATHMM, while pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—AlphaMissense‑Optimized, Rosetta, and Foldetta—are treated as unavailable. High‑accuracy assessments show the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifying the variant as Likely Pathogenic, whereas AlphaMissense‑Optimized and Foldetta provide no definitive verdict. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.127496 | Structured | 0.343480 | Uncertain | 0.822 | 0.333 | 0.000 | -8.619 | Likely Pathogenic | 0.796 | Likely Pathogenic | Ambiguous | 0.49 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.50 | Ambiguous | 0.28 | Likely Benign | 0.713 | Likely Pathogenic | -3.43 | Deleterious | 0.984 | Probably Damaging | 0.967 | Probably Damaging | 5.84 | Benign | 0.10 | Tolerated | 0.1155 | 0.5066 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.721A>G | K241E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K241E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include SIFT and FATHMM, whereas a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a deleterious interpretation: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains uncertain. Overall, the preponderance of evidence from multiple independent 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 | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -12.582 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.75 | Ambiguous | 0.1 | 1.36 | Ambiguous | 1.06 | Ambiguous | 0.68 | Ambiguous | 0.878 | Likely Pathogenic | -3.43 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 6.00 | Benign | 0.10 | Tolerated | 0.3610 | 0.1179 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.722A>G | K241R 2D AIThe SynGAP1 missense variant K241R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) 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 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 | PH | 0.196879 | Structured | 0.349250 | Uncertain | 0.797 | 0.347 | 0.000 | -4.615 | Likely Benign | 0.444 | Ambiguous | Likely Benign | -0.23 | Likely Benign | 0.5 | -0.03 | Likely Benign | -0.13 | Likely Benign | 0.43 | Likely Benign | 0.602 | Likely Pathogenic | -2.12 | Neutral | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 5.89 | Benign | 0.14 | Tolerated | 0.4571 | 0.1242 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.727A>C | I243L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I243L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from AlphaMissense‑Default and ESM1b, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; and Foldetta also predicts benign. Overall, 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. | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -7.890 | In-Between | 0.524 | Ambiguous | Likely Benign | -0.03 | Likely Benign | 0.2 | -0.35 | Likely Benign | -0.19 | Likely Benign | 0.32 | Likely Benign | 0.380 | Likely Benign | -0.33 | Neutral | 0.048 | Benign | 0.039 | Benign | 5.74 | Benign | 0.19 | Tolerated | 0.0626 | 0.2891 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.727A>G | I243V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243V is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and ESM1b. FoldX and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -8.237 | Likely Pathogenic | 0.314 | Likely Benign | Likely Benign | 1.09 | Ambiguous | 0.1 | 0.19 | Likely Benign | 0.64 | Ambiguous | 0.39 | Likely Benign | 0.445 | Likely Benign | -0.39 | Neutral | 0.617 | Possibly Damaging | 0.140 | Benign | 5.71 | Benign | 0.15 | Tolerated | 0.1019 | 0.2591 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.729T>G | I243M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I243M has no ClinVar entry (ClinVar status: not reported) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign”; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign effect. Overall, the consensus of the majority of tools, including the high‑accuracy methods, indicates that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.363090 | Structured | 0.344471 | Uncertain | 0.842 | 0.347 | 0.000 | -4.305 | Likely Benign | 0.175 | Likely Benign | Likely Benign | 0.09 | Likely Benign | 0.1 | 0.16 | Likely Benign | 0.13 | Likely Benign | -0.01 | Likely Benign | 0.474 | Likely Benign | 0.58 | Neutral | 0.985 | Probably Damaging | 0.798 | Possibly Damaging | 5.61 | Benign | 0.94 | Tolerated | 0.0553 | 0.2200 | 2 | 1 | -2.6 | 18.03 | |||||||||||||||||||||||||||||
| c.730G>A | E244K 2D AISynGAP1 missense variant E244K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign predictions come from FoldX, Rosetta, Foldetta, SIFT, and FATHMM, whereas pathogenic predictions are reported by REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). The high‑accuracy methods give a clearer picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. With the majority of consensus tools leaning toward pathogenic and the two high‑accuracy pathogenic predictions outweighing the benign Foldetta result, the variant is most likely pathogenic. This assessment 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 | PH | 0.450668 | Structured | 0.329406 | Uncertain | 0.778 | 0.360 | 0.000 | -13.975 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 1.0 | 0.45 | Likely Benign | 0.43 | Likely Benign | 0.80 | Ambiguous | 0.841 | Likely Pathogenic | -3.37 | Deleterious | 0.990 | Probably Damaging | 0.760 | Possibly Damaging | 5.82 | Benign | 0.07 | Tolerated | 0.1887 | 0.6177 | 0 | 1 | -0.4 | -0.94 | |||||||||||||||||||||||||||||
| c.733A>G | N245D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245D is 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, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools, premPS and ESM1b, return 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. Overall, the majority of predictions (six pathogenic vs five benign) and the consensus of high‑accuracy methods lean toward a pathogenic interpretation. 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. | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -7.847 | In-Between | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.27 | Likely Benign | 0.0 | 0.09 | Likely Benign | 0.18 | Likely Benign | 0.79 | Ambiguous | 0.712 | Likely Pathogenic | -3.62 | Deleterious | 0.982 | Probably Damaging | 0.679 | Possibly Damaging | 5.84 | Benign | 0.13 | Tolerated | 0.1953 | 0.4599 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.734A>G | N245S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245S is 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, polyPhen‑2 HumVar, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence (8 benign vs. 5 pathogenic) supports a benign classification. This conclusion does not contradict ClinVar, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -6.792 | Likely Benign | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.15 | Likely Benign | 0.42 | Likely Benign | 0.524 | Likely Pathogenic | -3.75 | Deleterious | 0.787 | Possibly Damaging | 0.404 | Benign | 5.90 | Benign | 0.07 | Tolerated | 0.3557 | 0.7229 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.739C>A | Q247K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247K (PH domain) is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are REVEL, polyPhen2_HumDiv, and ESM1b. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, favors a benign outcome (2 benign vs. 1 pathogenic). High‑accuracy methods all support benignity: AlphaMissense‑Optimized is benign, the SGM Consensus is benign, and Foldetta (combining FoldX‑MD and Rosetta) is benign. Uncertain results from AlphaMissense‑Default and Rosetta are treated as unavailable. Overall, the collective evidence points to a benign impact for Q247K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -10.377 | Likely Pathogenic | 0.502 | Ambiguous | Likely Benign | -0.28 | Likely Benign | 0.1 | 0.74 | Ambiguous | 0.23 | Likely Benign | -0.13 | Likely Benign | 0.529 | Likely Pathogenic | -0.44 | Neutral | 0.787 | Possibly Damaging | 0.351 | Benign | 5.89 | Benign | 0.13 | Tolerated | 0.1366 | 0.2758 | 1 | 1 | -0.4 | 0.04 | ||||||||||||||||||||||||||||||
| c.740A>G | Q247R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain predictions come from premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy methods, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -4.022 | Likely Benign | 0.442 | Ambiguous | Likely Benign | -0.38 | Likely Benign | 0.0 | 0.21 | Likely Benign | -0.09 | Likely Benign | -0.91 | Ambiguous | 0.471 | Likely Benign | 1.22 | Neutral | 0.948 | Possibly Damaging | 0.533 | Possibly Damaging | 5.91 | Benign | 1.00 | Tolerated | 0.1196 | 0.1324 | 1 | 1 | -1.0 | 28.06 | |||||||||||||||||||||||||||||
| c.745G>A | A249T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A249T is listed in ClinVar (ID 1031675.0) with an uncertain significance annotation and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, and FATHMM, whereas polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default predict a pathogenic outcome. Predictions that are inconclusive are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the balance of evidence favors a benign interpretation, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | Uncertain | 1 | -3.564 | Likely Benign | 0.805 | Likely Pathogenic | Ambiguous | 1.50 | Ambiguous | 0.6 | 1.39 | Ambiguous | 1.45 | Ambiguous | 0.30 | Likely Benign | 0.487 | Likely Benign | -0.96 | Neutral | 0.990 | Probably Damaging | 0.815 | Possibly Damaging | 5.65 | Benign | 0.40 | Tolerated | 3.39 | 15 | 0.0909 | 0.4972 | 1 | 0 | -2.5 | 30.03 | 214.5 | -43.3 | 0.0 | 0.0 | 0.5 | 0.2 | X | Potentially Benign | The methyl group of Ala249, located on the surface of an α helix (res. Ala236-Val250) facing an anti-parallel β sheet strand (res. Ile205-Val209), packs against nearby hydrophobic residues such as Leu200, Leu246, and Val250. In the variant simulations, the hydroxyl group of Thr249, which is not suitable for hydrophobic packing, forms a stable hydrogen bond with the backbone carbonyl of Asn245 in the same helix. Although this interaction could theoretically weaken the structural integrity of the α helix, this destabilizing effect is not observed in the variant simulations. | ||||||||||||||||
| c.745G>T | A249S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. Protein‑stability assessments are mixed: FoldX indicates a benign effect, while Rosetta and Foldetta are uncertain. High‑accuracy predictions show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the preponderance of evidence—including the high‑accuracy tools—suggests that A249S is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -5.707 | Likely Benign | 0.634 | Likely Pathogenic | Likely Benign | 0.48 | Likely Benign | 0.3 | 0.84 | Ambiguous | 0.66 | Ambiguous | 0.33 | Likely Benign | 0.465 | Likely Benign | -1.40 | Neutral | 0.990 | Probably Damaging | 0.681 | Possibly Damaging | 5.63 | Benign | 0.19 | Tolerated | 0.1962 | 0.3393 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.746C>A | A249E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A249E has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are SIFT and FATHMM. The majority of other in‑silico predictors (SGM‑Consensus, REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) classify the variant as pathogenic; FoldX is uncertain and is not counted as evidence for either side. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Based on the preponderance of pathogenic predictions and the absence of benign evidence, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.505461 | Disordered | 0.255452 | Uncertain | 0.810 | 0.336 | 0.125 | -13.519 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 1.60 | Ambiguous | 1.2 | 2.59 | Destabilizing | 2.10 | Destabilizing | 1.02 | Destabilizing | 0.818 | Likely Pathogenic | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.64 | Benign | 0.09 | Tolerated | 0.0799 | 0.1509 | 0 | -1 | -5.3 | 58.04 | |||||||||||||||||||||||||||||
| c.748G>A | V250I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V250I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the change as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy tools likewise predict a benign effect: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -6.696 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.44 | Likely Benign | 0.1 | -0.01 | Likely Benign | -0.23 | Likely Benign | 0.35 | Likely Benign | 0.362 | Likely Benign | -0.79 | Neutral | 0.384 | Benign | 0.070 | Benign | 6.09 | Benign | 0.13 | Tolerated | 0.0571 | 0.3644 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.751A>C | K251Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar, while premPS and AlphaMissense‑Default are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Taken together, the majority of evidence supports a benign classification for K251Q, and this conclusion does not contradict the absence of a ClinVar entry. Based on the aggregate predictions, K251Q is most likely benign, and this is consistent with its absence from ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -5.869 | Likely Benign | 0.362 | Ambiguous | Likely Benign | 0.36 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.39 | Likely Benign | -0.62 | Ambiguous | 0.465 | Likely Benign | 0.55 | Neutral | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.86 | Benign | 0.63 | Tolerated | 0.4466 | 0.1085 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.751A>G | K251E 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K251E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, PROVEAN, SIFT, and FATHMM, while those that agree on a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, AlphaMissense‑Optimized) give uncertain results. High‑accuracy methods are likewise inconclusive: AlphaMissense‑Optimized is uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a tie, and Foldetta is uncertain. Overall, the majority of available predictions lean toward pathogenicity, with a small but notable benign signal. Therefore, the variant is most likely pathogenic based on current computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -12.812 | Likely Pathogenic | 0.906 | Likely Pathogenic | Ambiguous | 0.88 | Ambiguous | 0.2 | 0.99 | Ambiguous | 0.94 | Ambiguous | 0.40 | Likely Benign | 0.571 | Likely Pathogenic | -0.54 | Neutral | 0.970 | Probably Damaging | 0.584 | Possibly Damaging | 5.80 | Benign | 0.46 | Tolerated | 0.3929 | 0.0860 | 0 | 1 | 0.4 | 0.94 | ||||||||||||||||||||||||||||||
| c.752A>C | K251T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, whereas a majority of tools predict a pathogenic impact: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results are FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show that the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) supports a pathogenic prediction, while AlphaMissense‑Optimized and Foldetta remain uncertain. Overall, the balance of evidence favors a pathogenic effect for K251T, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -10.552 | Likely Pathogenic | 0.841 | Likely Pathogenic | Ambiguous | 1.21 | Ambiguous | 0.4 | 0.50 | Ambiguous | 0.86 | Ambiguous | 0.46 | Likely Benign | 0.742 | Likely Pathogenic | -2.72 | Deleterious | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 5.76 | Benign | 0.28 | Tolerated | 0.2353 | 0.2852 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.752A>G | K251R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251R is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Rosetta and Foldetta give uncertain results. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -4.355 | Likely Benign | 0.123 | Likely Benign | Likely Benign | -0.37 | Likely Benign | 0.0 | -0.64 | Ambiguous | -0.51 | Ambiguous | 0.14 | Likely Benign | 0.531 | Likely Pathogenic | -0.61 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.92 | Benign | 0.34 | Tolerated | 0.4756 | 0.1049 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.753G>C | K251N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM (nine tools). Only AlphaMissense‑Default predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the preponderance of evidence indicates that K251N is most likely benign, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -7.978 | In-Between | 0.930 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.25 | Likely Benign | 0.32 | Likely Benign | 0.298 | Likely Benign | -1.29 | Neutral | 0.384 | Benign | 0.070 | Benign | 5.73 | Benign | 0.39 | Tolerated | 0.3848 | 0.1196 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.753G>T | K251N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K251N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM (nine tools). Only AlphaMissense‑Default predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Optimized are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the preponderance of evidence indicates that K251N is most likely benign, and this conclusion does not contradict the current ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.226632 | Uncertain | 0.758 | 0.312 | 0.125 | -7.978 | In-Between | 0.930 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.25 | Likely Benign | 0.32 | Likely Benign | 0.298 | Likely Benign | -1.29 | Neutral | 0.384 | Benign | 0.070 | Benign | 5.73 | Benign | 0.39 | Tolerated | 0.3848 | 0.1196 | 1 | 0 | 0.4 | -14.07 | ||||||||||||||||||||||||||||||
| c.757A>G | N253D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N253D is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on benign effects include FoldX, Rosetta, Foldetta, premPS, SIFT, and FATHMM, while those that predict pathogenicity are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicating likely pathogenic, whereas Foldetta predicts a benign effect on protein stability. Overall, the majority of tools (8/15) favor a pathogenic outcome, with no conflict with ClinVar status because the variant is not yet catalogued. Thus, the variant is most likely pathogenic based on current computational predictions, and this assessment does not contradict any existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -14.105 | Likely Pathogenic | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.25 | Likely Benign | 0.0 | 0.37 | Likely Benign | 0.31 | Likely Benign | 0.09 | Likely Benign | 0.742 | Likely Pathogenic | -4.13 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.60 | Benign | 0.09 | Tolerated | 0.2248 | 0.5186 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.758A>C | N253T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253T is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, whereas the majority of tools (SGM‑Consensus, REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default) predict a pathogenic outcome. High‑accuracy methods give a consistent pathogenic signal: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Pathogenic,” and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. AlphaMissense‑Optimized is uncertain and is treated as unavailable. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -11.656 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 1.96 | Ambiguous | 0.3 | 2.67 | Destabilizing | 2.32 | Destabilizing | 0.16 | Likely Benign | 0.739 | Likely Pathogenic | -5.01 | Deleterious | 0.993 | Probably Damaging | 0.971 | Probably Damaging | 5.54 | Benign | 0.06 | Tolerated | 0.1640 | 0.8665 | 0 | 0 | 2.8 | -13.00 | |||||||||||||||||||||||||||||
| c.758A>G | N253S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253S is listed in ClinVar with no submitted interpretation and is present in gnomAD (ID 6‑33435609‑A‑G). Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. Predictions that are uncertain or inconclusive are FoldX, Rosetta, Foldetta, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also inconclusive. Overall, the evidence is mixed, but the single high‑accuracy tool that is available points to a benign effect. Therefore, the variant is most likely benign based on current predictions, and this assessment does not contradict the ClinVar status, which remains unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | 6-33435609-A-G | -7.197 | In-Between | 0.541 | Ambiguous | Likely Benign | 0.60 | Ambiguous | 0.1 | 1.19 | Ambiguous | 0.90 | Ambiguous | -0.03 | Likely Benign | 0.716 | Likely Pathogenic | -4.26 | Deleterious | 0.993 | Probably Damaging | 0.956 | Probably Damaging | 5.56 | Benign | 0.09 | Tolerated | 3.39 | 15 | 0.3960 | 0.7764 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||
| c.760A>C | K254Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K254Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Foldetta, SIFT, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Rosetta and premPS, give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No prediction or folding stability result is missing or inconclusive. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -12.332 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 0.13 | Likely Benign | 0.1 | -0.61 | Ambiguous | -0.24 | Likely Benign | 0.90 | Ambiguous | 0.737 | Likely Pathogenic | -3.04 | Deleterious | 0.997 | Probably Damaging | 0.879 | Possibly Damaging | 5.91 | Benign | 0.11 | Tolerated | 0.3749 | 0.1483 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.761A>C | K254T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K254T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic calls come from REVEL, PROVEAN, both polyPhen‑2 HumDiv and HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Benign predictions are limited to SIFT and FATHMM. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a pathogenic effect for K254T, and this conclusion does not conflict with ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -13.793 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.51 | Ambiguous | 0.0 | 1.92 | Ambiguous | 1.22 | Ambiguous | 0.62 | Ambiguous | 0.883 | Likely Pathogenic | -5.14 | Deleterious | 0.970 | Probably Damaging | 0.749 | Possibly Damaging | 5.88 | Benign | 0.06 | Tolerated | 0.1825 | 0.2562 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.761A>G | K254R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K254R missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (2 benign vs. 1 pathogenic, 1 uncertain); Foldetta is uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.513880 | Disordered | 0.207751 | Uncertain | 0.799 | 0.285 | 0.375 | -11.064 | Likely Pathogenic | 0.528 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.1 | -1.13 | Ambiguous | -0.79 | Ambiguous | 0.76 | Ambiguous | 0.604 | Likely Pathogenic | -2.36 | Neutral | 0.970 | Probably Damaging | 0.681 | Possibly Damaging | 5.81 | Benign | 0.09 | Tolerated | 0.4070 | 0.1658 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.765C>A | D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change D255E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, and FATHMM. Those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is also inconclusive. Overall, the majority of available predictions (seven pathogenic vs. four benign) point to a likely pathogenic impact. This conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -6.876 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.90 | Ambiguous | 0.85 | Ambiguous | 0.15 | Likely Benign | 0.508 | Likely Pathogenic | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.89 | Benign | 0.08 | Tolerated | 0.1365 | 0.5067 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||
| c.765C>G | D255E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D255E is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, and FATHMM, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The remaining tools (FoldX, Rosetta, Foldetta) provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs. 2 benign), and Foldetta is also inconclusive. Overall, the majority of available predictions (7 pathogenic vs. 4 benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.219132 | Uncertain | 0.801 | 0.273 | 0.250 | -6.876 | Likely Benign | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.80 | Ambiguous | 0.3 | 0.90 | Ambiguous | 0.85 | Ambiguous | 0.15 | Likely Benign | 0.509 | Likely Pathogenic | -2.98 | Deleterious | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.89 | Benign | 0.08 | Tolerated | 0.1365 | 0.5067 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||
| c.769A>C | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact; Rosetta and Foldetta are uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for S257R. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.754 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.769A>G | S257G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257G is not reported in ClinVar (ClinVar status: None) and has no entry in gnomAD (gnomAD status: None). Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized. In contrast, a majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and the SGM‑Consensus score (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). High‑accuracy assessments further support this view: AlphaMissense‑Optimized indicates a benign change, whereas the SGM‑Consensus (majority vote) indicates likely pathogenic. The Foldetta stability prediction is unavailable and therefore does not influence the overall assessment. Based on the preponderance of pathogenic predictions and the lack of any ClinVar annotation, the variant is most likely pathogenic, with no contradiction from existing ClinVar data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.206 | Likely Pathogenic | 0.624 | Likely Pathogenic | Likely Benign | 0.61 | Ambiguous | 0.3 | 0.60 | Ambiguous | 0.61 | Ambiguous | 0.62 | Ambiguous | 0.703 | Likely Pathogenic | -2.95 | Deleterious | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 5.79 | Benign | 0.11 | Tolerated | 0.2087 | 0.3589 | 1 | 0 | 0.4 | -30.03 | |||||||||||||||||||||||||||||
| c.769A>T | S257C 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257C is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Foldetta, Rosetta) and pathogenic predictions (REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar). The high‑accuracy consensus methods—AlphaMissense‑Optimized, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta—each indicate a benign effect. No folding‑stability assessment is available beyond the benign Foldetta result. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of a ClinVar assertion. Thus, the variant is most likely benign, and this is not contradicted by ClinVar status, which has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -3.553 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.4 | -0.33 | Likely Benign | 0.09 | Likely Benign | -0.46 | Likely Benign | 0.611 | Likely Pathogenic | 0.02 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 5.76 | Benign | 0.18 | Tolerated | 0.0880 | 0.5151 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||
| c.770G>A | S257N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S257N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split consensus: benign calls come from FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and FATHMM, while pathogenic calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: premPS and AlphaMissense‑Optimized. High‑accuracy assessments give an inconclusive SGM Consensus (a tie between AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), an uncertain AlphaMissense‑Optimized result, and a benign Foldetta prediction. No evidence of pathogenicity is supported by the protein‑stability analysis, which indicates a benign effect. Overall, the predictions are mixed, but the majority of high‑accuracy tools lean toward a benign interpretation. This assessment does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -10.508 | Likely Pathogenic | 0.820 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.1 | -0.18 | Likely Benign | 0.04 | Likely Benign | 0.85 | Ambiguous | 0.533 | Likely Pathogenic | -2.30 | Neutral | 0.993 | Probably Damaging | 0.968 | Probably Damaging | 5.82 | Benign | 0.16 | Tolerated | 0.0985 | 0.3596 | 1 | 1 | -2.7 | 27.03 | ||||||||||||||||||||||||||||||
| c.770G>C | S257T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority benign) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that S257T is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -8.603 | Likely Pathogenic | 0.243 | Likely Benign | Likely Benign | 0.42 | Likely Benign | 0.1 | -0.16 | Likely Benign | 0.13 | Likely Benign | 0.06 | Likely Benign | 0.472 | Likely Benign | -1.58 | Neutral | 0.982 | Probably Damaging | 0.952 | Probably Damaging | 5.83 | Benign | 0.48 | Tolerated | 0.1073 | 0.4898 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.770G>T | S257I 2D AIThe SynGAP1 missense variant S257I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, FATHMM, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic effect comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta predicting a benign outcome. FoldX and Rosetta results are uncertain and therefore not considered. Overall, the balance of evidence leans toward a pathogenic interpretation, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -12.126 | Likely Pathogenic | 0.595 | Likely Pathogenic | Likely Benign | 0.78 | Ambiguous | 1.0 | -1.17 | Ambiguous | -0.20 | Likely Benign | 0.30 | Likely Benign | 0.739 | Likely Pathogenic | -2.97 | Deleterious | 0.998 | Probably Damaging | 0.991 | Probably Damaging | 5.81 | Benign | 0.07 | Tolerated | 0.0681 | 0.5209 | -1 | -2 | 5.3 | 26.08 | |||||||||||||||||||||||||||||
| c.771C>A | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools show a split: benign calls come from FoldX, premPS, SIFT, and FATHMM, whereas pathogenic calls are made by REVEL, PROVEAN, both polyPhen‑2 versions, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain outcomes include Rosetta and Foldetta. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Pathogenic,” and Foldetta’s stability analysis is inconclusive. Overall, the majority of reliable predictors indicate a pathogenic impact, and this conclusion does not conflict with the absence of a ClinVar classification. Therefore, the variant is most likely pathogenic, and this assessment is consistent with its lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.707 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.771C>G | S257R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S257R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, premPS, SIFT, and FATHMM, whereas those that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta as uncertain. Overall, the majority of evaluated tools (7 pathogenic vs. 4 benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this prediction does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.384043 | Structured | 0.258293 | Uncertain | 0.847 | 0.272 | 0.250 | -11.746 | Likely Pathogenic | 0.992 | Likely Pathogenic | Likely Pathogenic | -0.18 | Likely Benign | 0.0 | -1.33 | Ambiguous | -0.76 | Ambiguous | 0.29 | Likely Benign | 0.707 | Likely Pathogenic | -3.38 | Deleterious | 0.998 | Probably Damaging | 0.986 | Probably Damaging | 5.81 | Benign | 0.13 | Tolerated | 0.0762 | 0.3068 | 0 | -1 | -3.7 | 69.11 | |||||||||||||||||||||||||||||
| c.778G>A | V260I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260I missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts benign. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.254060 | Structured | 0.382651 | Uncertain | 0.888 | 0.259 | 0.250 | -7.525 | In-Between | 0.104 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | 0.27 | Likely Benign | 0.06 | Likely Benign | -0.14 | Likely Benign | 0.404 | Likely Benign | -0.85 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.83 | Benign | 0.19 | Tolerated | 0.0559 | 0.3704 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.778G>C | V260L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260L missense change is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from FoldX, Rosetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, polyPhen‑2 (HumDiv and HumVar) and ESM1b. The high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, and Foldetta predicts a benign effect on protein stability. No prediction is missing or inconclusive. Overall, the evidence points to a benign effect for V260L, 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 | -8.785 | Likely Pathogenic | 0.416 | Ambiguous | Likely Benign | -0.26 | Likely Benign | 0.1 | 0.15 | Likely Benign | -0.06 | Likely Benign | 0.25 | Likely Benign | 0.532 | Likely Pathogenic | -1.84 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.90 | Benign | 0.11 | Tolerated | 0.0730 | 0.4360 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.778G>T | V260L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260L 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, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the aggregate 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. | C2 | 0.254060 | Structured | 0.382651 | Uncertain | 0.888 | 0.259 | 0.250 | -8.785 | Likely Pathogenic | 0.416 | Ambiguous | Likely Benign | -0.26 | Likely Benign | 0.1 | 0.15 | Likely Benign | -0.06 | Likely Benign | 0.25 | Likely Benign | 0.532 | Likely Pathogenic | -1.84 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.90 | Benign | 0.11 | Tolerated | 0.0730 | 0.4360 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.779T>A | V260E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V260E is not reported in ClinVar and has no entries in gnomAD. Prediction tools that indicate a benign effect include FoldX, Rosetta, Foldetta, SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) labeling it likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign impact on protein stability. Overall, the majority of computational evidence points toward a pathogenic interpretation, and this conclusion is not contradicted by the ClinVar status. Thus, the variant is most likely pathogenic, and 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 | C2 | 0.254060 | Structured | 0.382651 | Uncertain | 0.888 | 0.259 | 0.250 | -9.516 | Likely Pathogenic | 0.667 | Likely Pathogenic | Likely Benign | -0.02 | Likely Benign | 0.1 | 0.32 | Likely Benign | 0.15 | Likely Benign | 1.10 | Destabilizing | 0.848 | Likely Pathogenic | -3.66 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 5.79 | Benign | 0.09 | Tolerated | 0.0846 | 0.1636 | -2 | -2 | -7.7 | 29.98 | |||||||||||||||||||||||||||||
| c.779T>C | V260A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V260A missense variant is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, the SGM‑Consensus (majority vote), and Foldetta. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Two tools (premPS and AlphaMissense‑Default) give uncertain results. High‑accuracy assessments—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta—all indicate a benign outcome. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.254060 | Structured | 0.382651 | Uncertain | 0.888 | 0.259 | 0.250 | -3.271 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.38 | Likely Benign | 0.0 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.81 | Ambiguous | 0.487 | Likely Benign | -1.41 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.87 | Benign | 0.33 | Tolerated | 0.2676 | 0.1903 | 0 | 0 | -2.4 | -28.05 | |||||||||||||||||||||||||||||
| c.782A>T | D261V 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and FATHMM, while those that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. 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 majority of available predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -12.138 | Likely Pathogenic | 0.923 | Likely Pathogenic | Ambiguous | 1.72 | Ambiguous | 0.6 | -0.68 | Ambiguous | 0.52 | Ambiguous | -0.01 | Likely Benign | 0.869 | Likely Pathogenic | -5.50 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 5.73 | Benign | 0.08 | Tolerated | 0.0553 | 0.4734 | -2 | -3 | 7.7 | -15.96 | |||||||||||||||||||||||||||||
| c.783C>A | D261E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The high‑accuracy consensus from AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) both indicate a benign outcome, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is inconclusive. Overall, the majority of evidence points to a benign impact. This assessment is consistent with the absence of ClinVar annotation and does not contradict any existing database status. Based on the predictions, the variant is most likely benign, and this does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -2.646 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.8 | 0.79 | Ambiguous | 1.12 | Ambiguous | -0.03 | Likely Benign | 0.377 | Likely Benign | 0.20 | Neutral | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.88 | Benign | 1.00 | Tolerated | 0.0963 | 0.4359 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.783C>G | D261E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D261E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Protein‑stability calculations from FoldX and Rosetta are uncertain. Overall, the majority of evidence points to a benign impact, which is consistent with the absence of a ClinVar claim and gnomAD observation. 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 | C2 | 0.284882 | Structured | 0.422514 | Uncertain | 0.883 | 0.264 | 0.125 | -2.646 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.8 | 0.79 | Ambiguous | 1.12 | Ambiguous | -0.03 | Likely Benign | 0.377 | Likely Benign | 0.20 | Neutral | 0.994 | Probably Damaging | 0.978 | Probably Damaging | 5.88 | Benign | 1.00 | Tolerated | 0.0963 | 0.4359 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.784A>C | N262H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, Rosetta, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, and polyPhen‑2 HumVar. FoldX and Foldetta results are uncertain, providing no clear direction. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign impact for this variant, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -6.932 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 1.82 | Ambiguous | 0.5 | 0.41 | Likely Benign | 1.12 | Ambiguous | 0.33 | Likely Benign | 0.694 | Likely Pathogenic | -3.44 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 5.81 | Benign | 0.41 | Tolerated | 0.1122 | 0.4860 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.785A>C | N262T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262T has no ClinVar record and is not reported in gnomAD. Functional prediction tools cluster into three groups: benign predictions come from SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and ESM1b; the remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta’s stability analysis is uncertain. Overall, the balance of evidence leans toward pathogenicity, with no conflict with ClinVar status (which is absent). 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. | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -11.478 | Likely Pathogenic | 0.544 | Ambiguous | Likely Benign | 1.40 | Ambiguous | 0.3 | 1.44 | Ambiguous | 1.42 | Ambiguous | 0.74 | Ambiguous | 0.723 | Likely Pathogenic | -5.23 | Deleterious | 0.997 | Probably Damaging | 0.980 | Probably Damaging | 5.88 | Benign | 0.19 | Tolerated | 0.1055 | 0.5164 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.785A>G | N262S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N262S is not listed in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools cluster into two groups: benign predictions come from SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Uncertain results are reported by FoldX, Rosetta, Foldetta, and premPS. High‑accuracy methods give the following: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is uncertain. Consequently, the overall evidence is mixed, with a slight tilt toward pathogenicity because five tools predict pathogenic while four predict benign. The variant is most likely pathogenic based on the current predictions, and 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. | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -8.841 | Likely Pathogenic | 0.182 | Likely Benign | Likely Benign | 0.91 | Ambiguous | 0.2 | 0.90 | Ambiguous | 0.91 | Ambiguous | 0.69 | Ambiguous | 0.638 | Likely Pathogenic | -4.31 | Deleterious | 0.997 | Probably Damaging | 0.970 | Probably Damaging | 5.84 | Benign | 0.16 | Tolerated | 0.3101 | 0.5158 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||||||||
| c.787G>C | V263L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive are Rosetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -6.599 | Likely Benign | 0.275 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.40 | Likely Benign | 0.66 | Ambiguous | 0.453 | Likely Benign | -1.26 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.85 | Benign | 0.18 | Tolerated | 0.0759 | 0.3950 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.787G>T | V263L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V263L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Predictions that are inconclusive are Rosetta (Uncertain) and premPS (Uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.356141 | Uncertain | 0.918 | 0.257 | 0.000 | -6.599 | Likely Benign | 0.275 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.1 | -0.63 | Ambiguous | -0.40 | Likely Benign | 0.66 | Ambiguous | 0.453 | Likely Benign | -1.26 | Neutral | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 5.85 | Benign | 0.18 | Tolerated | 0.0759 | 0.3950 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.794A>C | K265T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K265T missense variant is reported in gnomAD (ID 6‑33437699‑A‑C) but has no ClinVar entry. Prediction tools that classify the variant as benign include REVEL, SIFT, and Rosetta. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Four tools give uncertain results: FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | 6-33437699-A-C | 1 | 6.20e-7 | -9.425 | Likely Pathogenic | 0.839 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.1 | 0.37 | Likely Benign | 0.68 | Ambiguous | 0.83 | Ambiguous | 0.441 | Likely Benign | -3.75 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.07 | Tolerated | 3.38 | 18 | 0.2042 | 0.3178 | -1 | 0 | 3.2 | -27.07 | ||||||||||||||||||||||||
| c.794A>G | K265R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K265R is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster into two groups: benign predictions include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. No prediction or stability result is missing or inconclusive. Based on the aggregate evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.209395 | Structured | 0.309758 | Uncertain | 0.936 | 0.275 | 0.000 | -3.366 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.04 | Likely Benign | 0.1 | -0.44 | Likely Benign | -0.20 | Likely Benign | 0.30 | Likely Benign | 0.223 | Likely Benign | -1.08 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.90 | Pathogenic | 0.36 | Tolerated | 0.4713 | 0.0976 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.796C>A | L266M 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L266M is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Two tools remain uncertain: premPS and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts a benign effect. Overall, the majority of tools (six benign vs. four pathogenic, with two uncertain) lean toward a benign classification, and this conclusion is not contradicted by ClinVar status. Thus, the variant is most likely benign based on the collective predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -9.740 | Likely Pathogenic | 0.362 | Ambiguous | Likely Benign | 0.07 | Likely Benign | 0.1 | -0.47 | Likely Benign | -0.20 | Likely Benign | 0.95 | Ambiguous | 0.288 | Likely Benign | -1.66 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.55 | Pathogenic | 0.07 | Tolerated | 0.0581 | 0.2853 | 4 | 2 | -1.9 | 18.03 | ||||||||||||||||||||||||||||||
| c.796C>G | L266V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L266V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are therefore considered unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic) and Foldetta is also inconclusive. Consequently, the variant is most likely benign based on the current predictions, and this assessment does not contradict ClinVar, which has no reported status for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.232838 | Structured | 0.297157 | Uncertain | 0.948 | 0.264 | 0.000 | -8.586 | Likely Pathogenic | 0.153 | Likely Benign | Likely Benign | 1.71 | Ambiguous | 0.1 | 0.97 | Ambiguous | 1.34 | Ambiguous | 1.32 | Destabilizing | 0.193 | Likely Benign | -2.20 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.37 | Pathogenic | 0.11 | Tolerated | 0.1152 | 0.2456 | 2 | 1 | 0.4 | -14.03 | ||||||||||||||||||||||||||||||
| c.800G>C | W267S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant W267S is not listed in ClinVar and has no allele in gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas the remaining 12 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all report pathogenicity; premPS is uncertain. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No prediction is missing or inconclusive. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.298060 | Uncertain | 0.943 | 0.274 | 0.000 | -12.833 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 3.42 | Destabilizing | 0.3 | 3.20 | Destabilizing | 3.31 | Destabilizing | 0.87 | Ambiguous | 0.593 | Likely Pathogenic | -12.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 2.03 | Pathogenic | 0.09 | Tolerated | 0.3809 | 0.1415 | -2 | -3 | 0.1 | -99.14 | |||||||||||||||||||||||||||||
| c.802A>G | I268V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I268V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or unavailable are FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign, while Foldetta’s stability analysis is uncertain. Overall, the majority of reliable predictors indicate a benign impact, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.216401 | Structured | 0.314336 | Uncertain | 0.951 | 0.264 | 0.000 | -4.553 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 1.46 | Ambiguous | 0.0 | 0.95 | Ambiguous | 1.21 | Ambiguous | 0.71 | Ambiguous | 0.139 | Likely Benign | -0.56 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 2.15 | Pathogenic | 0.71 | Tolerated | 0.0845 | 0.2489 | 4 | 3 | -0.3 | -14.03 | |||||||||||||||||||||||||||||
| c.805A>C | I269L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I269L missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized all predict benign. Pathogenicity is suggested by polyPhen‑2 (HumDiv and HumVar) and FATHMM, while ESM1b and AlphaMissense‑Default remain uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, Foldetta predicts benign stability, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to an equal split between benign and pathogenic signals. Overall, the balance of evidence favors a benign effect for I269L, 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. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -7.588 | In-Between | 0.470 | Ambiguous | Likely Benign | 0.00 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.10 | Likely Benign | 0.47 | Likely Benign | 0.348 | Likely Benign | -1.47 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.88 | Pathogenic | 0.28 | Tolerated | 0.0662 | 0.2817 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.805A>G | I269V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 I269V missense variant has no ClinVar record (ClinVar ID None) and is not reported in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Foldetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of tools lean toward a benign interpretation, but the high‑accuracy consensus indicates a pathogenic signal, leaving the variant’s clinical significance uncertain. This assessment does not contradict any existing ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -8.748 | Likely Pathogenic | 0.344 | Ambiguous | Likely Benign | 0.95 | Ambiguous | 0.0 | 0.49 | Likely Benign | 0.72 | Ambiguous | 0.71 | Ambiguous | 0.393 | Likely Benign | -0.72 | Neutral | 0.958 | Probably Damaging | 0.970 | Probably Damaging | 1.87 | Pathogenic | 0.10 | Tolerated | 0.0844 | 0.2859 | 4 | 3 | -0.3 | -14.03 | ||||||||||||||||||||||||||||||
| c.805A>T | I269L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two consensus groups: eight tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized) predict a benign effect, while three tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM) predict pathogenicity. Two tools (ESM1b, AlphaMissense‑Default) return uncertain results. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized classifies the variant as benign; Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign impact. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields no clear majority and is therefore unavailable as evidence. Overall, the preponderance of evidence supports a benign classification, which is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -7.588 | In-Between | 0.470 | Ambiguous | Likely Benign | 0.00 | Likely Benign | 0.0 | 0.19 | Likely Benign | 0.10 | Likely Benign | 0.47 | Likely Benign | 0.348 | Likely Benign | -1.47 | Neutral | 0.981 | Probably Damaging | 0.970 | Probably Damaging | 1.88 | Pathogenic | 0.28 | Tolerated | 0.0662 | 0.2817 | 2 | 2 | -0.7 | 0.00 | ||||||||||||||||||||||||||||||
| c.806T>A | I269K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT is the sole benign predictor, whereas the remaining methods—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive. FoldX and Rosetta individually report uncertain effects, and Foldetta remains unavailable. Overall, the consensus of the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -14.609 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.45 | Ambiguous | 0.1 | 1.86 | Ambiguous | 1.66 | Ambiguous | 1.55 | Destabilizing | 0.763 | Likely Pathogenic | -5.10 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.76 | Pathogenic | 0.06 | Tolerated | 0.0878 | 0.0713 | -2 | -3 | -8.4 | 15.01 | |||||||||||||||||||||||||||||
| c.806T>C | I269T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269T is not reported in ClinVar (no ClinVar entry) but is present in gnomAD (variant ID 6‑33437711‑T‑C). Among general in‑silico predictors, only SIFT classifies the change as benign, whereas the remaining tools that provide a definitive call (REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) all predict a pathogenic effect. High‑accuracy assessments give a more nuanced view: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also reports a pathogenic effect. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | 6-33437711-T-C | 2 | 1.24e-6 | -9.376 | Likely Pathogenic | 0.887 | Likely Pathogenic | Ambiguous | 1.97 | Ambiguous | 0.1 | 2.10 | Destabilizing | 2.04 | Destabilizing | 1.38 | Destabilizing | 0.727 | Likely Pathogenic | -3.70 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.72 | Pathogenic | 0.09 | Tolerated | 3.38 | 19 | 0.0833 | 0.0808 | -1 | 0 | -5.2 | -12.05 | ||||||||||||||||||||||||
| c.806T>G | I269R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant I269R is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: the benign group contains only SIFT, whereas the pathogenic group includes SGM‑Consensus (Likely Pathogenic), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. FoldX and Rosetta give uncertain results, and Foldetta is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as Likely Pathogenic, and Foldetta as unavailable. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.216401 | Structured | 0.343787 | Uncertain | 0.937 | 0.244 | 0.125 | -14.567 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 1.34 | Ambiguous | 0.1 | 1.99 | Ambiguous | 1.67 | Ambiguous | 1.50 | Destabilizing | 0.765 | Likely Pathogenic | -5.23 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.69 | Pathogenic | 0.07 | Tolerated | 0.1108 | 0.0870 | -2 | -3 | -9.0 | 43.03 | |||||||||||||||||||||||||||||
| c.817G>A | E273K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273K is not reported in ClinVar and is present in gnomAD (ID 6‑33437722‑G‑A). Functional prediction tools that agree on benign impact include REVEL, Rosetta, Foldetta, premPS, polyPhen‑2 HumVar, and SIFT. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Predictions marked uncertain are FoldX 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 benign. Overall, the majority of tools lean toward a benign effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.071867 | Structured | 0.398918 | Uncertain | 0.863 | 0.196 | 0.125 | 6-33437722-G-A | 1 | 6.20e-7 | -12.690 | Likely Pathogenic | 0.917 | Likely Pathogenic | Ambiguous | -0.57 | Ambiguous | 0.3 | -0.38 | Likely Benign | -0.48 | Likely Benign | 0.23 | Likely Benign | 0.205 | Likely Benign | -2.66 | Deleterious | 0.896 | Possibly Damaging | 0.415 | Benign | 1.77 | Pathogenic | 0.12 | Tolerated | 3.38 | 18 | 0.2312 | 0.2996 | 1 | 0 | -0.4 | -0.94 | ||||||||||||||||||||||||
| c.818A>G | E273G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E273G missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, premPS, SIFT, and ESM1b; pathogenic predictions from PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (FoldX, Rosetta, AlphaMissense‑Default, Foldetta) returned 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 a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels it pathogenic; Foldetta remains uncertain. Given the split between benign and pathogenic signals and the lack of a ClinVar classification, the variant is best described as of uncertain significance, with a slight inclination toward benign based on the most reliable single‑tool prediction. This assessment does not contradict any existing ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.071867 | Structured | 0.398918 | Uncertain | 0.863 | 0.196 | 0.125 | -4.784 | Likely Benign | 0.373 | Ambiguous | Likely Benign | -0.65 | Ambiguous | 0.2 | -0.93 | Ambiguous | -0.79 | Ambiguous | -0.46 | Likely Benign | 0.225 | Likely Benign | -2.71 | Deleterious | 0.896 | Possibly Damaging | 0.519 | Possibly Damaging | 1.95 | Pathogenic | 0.26 | Tolerated | 0.2763 | 0.3341 | 0 | -2 | 3.1 | -72.06 | ||||||||||||||||||||||||||||||
| c.819G>C | E273D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 E273D missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools largely agree on a benign effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate benign or likely benign. Only FATHMM predicts a pathogenic outcome, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign impact for E273D, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.071867 | Structured | 0.398918 | Uncertain | 0.863 | 0.196 | 0.125 | -1.811 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.26 | Likely Benign | 0.1 | -0.48 | Likely Benign | -0.11 | Likely Benign | -0.63 | Ambiguous | 0.094 | Likely Benign | 1.99 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 1.00 | Tolerated | 3.38 | 18 | 0.1711 | 0.1859 | 3 | 2 | 0.0 | -14.03 | 223.1 | 22.1 | 0.2 | 0.0 | 0.0 | 0.1 | X | Potentially Benign | The negatively charged residue Glu273, located in a β hairpin loop (res. Glu273-Lys278) that connects two anti-parallel β sheet strands, is replaced with another negatively charged residue, aspartate. Because the C2 domain loop faces the membrane surface, the potentially crucial role of the carboxylate group of Glu273 or Asp273 on SynGAP-membrane association cannot be fully explored via solvent-only simulations.As a minor note, the neighboring residue Arg272, which stacks with the indole ring of the Trp362 side chain and directly faces RasGTPase, forms a salt bridge more often with Asp273 than with the non-mutated Glu273 in the simulations. Regardless, due to the similar physicochemical properties of the WT and variant residues at the membrane interface, the residue swap is likely to be well tolerated. | ||||||||||||||||||
| c.819G>T | E273D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E273D is listed in ClinVar as Benign (ClinVar ID 1471608.0) and is present in gnomAD (variant ID 6‑33437724‑G‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while premPS is uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is Likely Benign. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction contradicts the ClinVar benign status; overall, the evidence strongly supports that E273D is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.071867 | Structured | 0.398918 | Uncertain | 0.863 | 0.196 | 0.125 | Benign | 1 | 6-33437724-G-T | 2 | 1.24e-6 | -1.811 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.26 | Likely Benign | 0.1 | -0.48 | Likely Benign | -0.11 | Likely Benign | -0.63 | Ambiguous | 0.092 | Likely Benign | 1.99 | Neutral | 0.004 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 1.00 | Tolerated | 3.38 | 18 | 0.1711 | 0.1859 | 3 | 2 | 0.0 | -14.03 | 223.1 | 22.1 | 0.2 | 0.0 | 0.0 | 0.1 | X | Potentially Benign | The negatively charged residue Glu273, located in a β hairpin loop (res. Glu273-Lys278) that connects two anti-parallel β sheet strands, is replaced with another negatively charged residue, aspartate. Because the C2 domain loop faces the membrane surface, the potentially crucial role of the carboxylate group of Glu273 or Asp273 on SynGAP-membrane association cannot be fully explored via solvent-only simulations.As a minor note, the neighboring residue Arg272, which stacks with the indole ring of the Trp362 side chain and directly faces RasGTPase, forms a salt bridge more often with Asp273 than with the non-mutated Glu273 in the simulations. Regardless, due to the similar physicochemical properties of the WT and variant residues at the membrane interface, the residue swap is likely to be well tolerated. | |||||||||||||
| c.823C>G | P275A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P275A is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33437728‑C‑G). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments are less decisive: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is uncertain. Consequently, the overall evidence leans toward a benign interpretation, with no ClinVar record to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.059222 | Structured | 0.353469 | Uncertain | 0.811 | 0.208 | 0.250 | 6-33437728-C-G | 1 | 6.20e-7 | -6.137 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 1.87 | Ambiguous | 0.2 | 1.11 | Ambiguous | 1.49 | Ambiguous | 0.50 | Likely Benign | 0.410 | Likely Benign | -4.95 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.79 | Pathogenic | 0.32 | Tolerated | 3.38 | 19 | 0.3475 | 0.3243 | -1 | 1 | 3.4 | -26.04 | |||||||||||||||||||||||||
| c.826C>G | P276A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P276A is reported in gnomAD (variant ID 6‑33437731‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The high‑accuracy consensus methods give a benign signal: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Overall, the majority of evidence points to a benign effect, and this assessment does not contradict any ClinVar status (none is available). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.037156 | Structured | 0.338937 | Uncertain | 0.724 | 0.230 | 0.250 | 6-33437731-C-G | 5 | 3.10e-6 | -3.414 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 1.42 | Ambiguous | 0.1 | 1.01 | Ambiguous | 1.22 | Ambiguous | 0.50 | Likely Benign | 0.187 | Likely Benign | -2.31 | Neutral | 0.044 | Benign | 0.030 | Benign | 1.98 | Pathogenic | 0.57 | Tolerated | 3.38 | 19 | 0.3149 | 0.3669 | -1 | 1 | 3.4 | -26.04 | ||||||||||||||||||||||||
| c.82T>A | S28T 2D AIThe SynGAP1 missense variant S28T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that the variant is most likely benign, and this conclusion is consistent with the lack of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -3.810 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.21 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.64 | Tolerated | 0.1874 | 0.6140 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.82T>G | S28A 2D AIThe SynGAP1 missense variant S28A is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -3.517 | Likely Benign | 0.063 | Likely Benign | Likely Benign | 0.039 | Likely Benign | 0.09 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.27 | Benign | 1.00 | Tolerated | 0.5194 | 0.4958 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||||||||||||
| c.830A>G | K277R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K277R is 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, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Rosetta gives an uncertain result. High‑accuracy methods give a benign prediction from AlphaMissense‑Optimized and from Foldetta; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it is a 2‑vs‑2 split. Overall, the majority of evidence (7 benign vs. 5 pathogenic) supports a benign classification. This consensus 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. | C2 | 0.061840 | Structured | 0.321811 | Uncertain | 0.649 | 0.247 | 0.250 | -6.652 | Likely Benign | 0.156 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.26 | Likely Benign | 0.06 | Likely Benign | 0.518 | Likely Pathogenic | -2.76 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.83 | Pathogenic | 0.06 | Tolerated | 0.4232 | 0.0678 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.832A>G | K278E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and SIFT, all of which score the substitution as tolerated. In contrast, a majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as damaging. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic verdict. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, predicts a benign effect. premPS is inconclusive and therefore not considered evidence. High‑accuracy assessments therefore show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as pathogenic, and Foldetta as benign. Overall, the preponderance of evidence from multiple independent predictors indicates that K278E is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -14.047 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.1 | 0.39 | Likely Benign | 0.40 | Likely Benign | 0.68 | Ambiguous | 0.463 | Likely Benign | -3.64 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.76 | Pathogenic | 0.06 | Tolerated | 0.3189 | 0.0492 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.833A>G | K278R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields an equal split of benign and pathogenic calls. Overall, the majority of evidence points to a benign impact. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -5.313 | Likely Benign | 0.216 | Likely Benign | Likely Benign | -0.05 | Likely Benign | 0.0 | 0.18 | Likely Benign | 0.07 | Likely Benign | 0.13 | Likely Benign | 0.282 | Likely Benign | -2.66 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.73 | Pathogenic | 0.10 | Tolerated | 0.3926 | 0.0489 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.834G>C | K278N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K278N is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the majority of tools support a pathogenic effect, so the variant is most likely pathogenic; this is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -10.611 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.23 | Likely Benign | 0.44 | Likely Benign | 0.255 | Likely Benign | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.81 | Pathogenic | 0.07 | Tolerated | 0.3071 | 0.0568 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.834G>T | K278N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K278N is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas tools that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. With a majority of evidence pointing to deleterious effects and no ClinVar annotation to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.120615 | Structured | 0.310130 | Uncertain | 0.748 | 0.253 | 0.125 | -10.611 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.40 | Likely Benign | 0.0 | 0.05 | Likely Benign | 0.23 | Likely Benign | 0.44 | Likely Benign | 0.255 | Likely Benign | -4.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.81 | Pathogenic | 0.07 | Tolerated | 0.3071 | 0.0568 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.836G>A | R279Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R279Q is reported in gnomAD (ID 6‑33437741‑G‑A) but has no ClinVar entry. Prediction tools that agree on a benign effect are SIFT and AlphaMissense‑Optimized; those that agree on a pathogenic effect are SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the majority of reliable predictors (nine pathogenic vs two benign) indicate a pathogenic effect. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.155435 | Structured | 0.309382 | Uncertain | 0.887 | 0.257 | 0.125 | 6-33437741-G-A | 6 | 3.72e-6 | -8.730 | Likely Pathogenic | 0.761 | Likely Pathogenic | Likely Benign | 1.37 | Ambiguous | 0.1 | 0.88 | Ambiguous | 1.13 | Ambiguous | 1.35 | Destabilizing | 0.554 | Likely Pathogenic | -2.61 | Deleterious | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.06 | Tolerated | 3.39 | 18 | 0.2680 | 0.1792 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||||
| c.838T>A | Y280N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y280N is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas all other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts pathogenicity. Based on the overwhelming consensus of pathogenic predictions and the absence of any benign consensus, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for Y280N. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.161087 | Structured | 0.321243 | Uncertain | 0.917 | 0.248 | 0.125 | -13.090 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.26 | Destabilizing | 0.2 | 4.18 | Destabilizing | 4.22 | Destabilizing | 1.82 | Destabilizing | 0.589 | Likely Pathogenic | -8.27 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.95 | Pathogenic | 0.06 | Tolerated | 0.1902 | 0.0212 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.83C>G | S28C 2D AIThe SynGAP1 missense variant S28C is not reported in ClinVar and is absent from gnomAD. In silico prediction tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No pathogenic predictions are present among the evaluated tools. High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are unavailable. Consequently, the variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | -4.800 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.021 | Likely Benign | -0.26 | Neutral | 0.022 | Benign | 0.004 | Benign | 4.13 | Benign | 0.11 | Tolerated | 0.1387 | 0.5741 | 0 | -1 | 3.3 | 16.06 | |||||||||||||||||||||||||||||||||||||||
| c.841T>A | Y281N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281N is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions are provided only by SIFT, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default—consistently predict pathogenicity. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized remains inconclusive, SGM‑Consensus is labeled Likely Pathogenic, and Foldetta predicts a destabilizing, pathogenic outcome. Overall, the collective evidence indicates that Y281N is most likely pathogenic, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -11.620 | Likely Pathogenic | 0.941 | Likely Pathogenic | Ambiguous | 3.29 | Destabilizing | 0.2 | 2.49 | Destabilizing | 2.89 | Destabilizing | 1.71 | Destabilizing | 0.713 | Likely Pathogenic | -6.20 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.99 | Pathogenic | 0.09 | Tolerated | 0.2494 | 0.1503 | -2 | -2 | -2.2 | -49.07 | |||||||||||||||||||||||||||||
| c.841T>C | Y281H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: SIFT classifies it as benign, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict pathogenicity. High‑accuracy methods provide a clearer picture: AlphaMissense‑Optimized is uncertain, SGM‑Consensus indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic folding instability. With the overwhelming consensus from most predictors and the high‑accuracy tools supporting a damaging effect, the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -8.522 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 2.65 | Destabilizing | 0.2 | 2.05 | Destabilizing | 2.35 | Destabilizing | 1.63 | Destabilizing | 0.717 | Likely Pathogenic | -3.82 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.99 | Pathogenic | 0.16 | Tolerated | 0.2651 | 0.1503 | 0 | 2 | -1.9 | -26.03 | |||||||||||||||||||||||||||||
| c.841T>G | Y281D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281D is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a deleterious effect: SIFT classifies it as benign, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) predict it to be pathogenic. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenicity; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts pathogenic. No tool yields an inconclusive result. Based on the collective predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status, as no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -15.506 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 4.27 | Destabilizing | 0.0 | 4.53 | Destabilizing | 4.40 | Destabilizing | 1.48 | Destabilizing | 0.813 | Likely Pathogenic | -6.73 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 0.98 | Pathogenic | 0.06 | Tolerated | 0.4173 | 0.1175 | -4 | -3 | -2.2 | -48.09 | |||||||||||||||||||||||||||||
| c.842A>C | Y281S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281S is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools cluster into two groups: the single benign prediction comes from SIFT, while the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—predict pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is Pathogenic. With the overwhelming majority of evidence indicating pathogenicity and 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 | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -9.541 | Likely Pathogenic | 0.847 | Likely Pathogenic | Ambiguous | 3.24 | Destabilizing | 0.3 | 3.02 | Destabilizing | 3.13 | Destabilizing | 1.59 | Destabilizing | 0.642 | Likely Pathogenic | -5.68 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.02 | Pathogenic | 0.12 | Tolerated | 0.4203 | 0.2543 | -3 | -2 | 0.5 | -76.10 | |||||||||||||||||||||||||||||
| c.842A>T | Y281F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y281F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign; Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No evidence from the uncertain FoldX result is considered. Overall, the consensus of high‑confidence tools points to a benign classification, which is consistent with the absence of ClinVar evidence and gnomAD data. Thus, the variant is most likely benign, and this conclusion does not contradict ClinVar status, which has no reported pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.098513 | Structured | 0.337647 | Uncertain | 0.927 | 0.254 | 0.000 | -3.991 | Likely Benign | 0.146 | Likely Benign | Likely Benign | 0.75 | Ambiguous | 0.2 | -0.26 | Likely Benign | 0.25 | Likely Benign | -0.37 | Likely Benign | 0.372 | Likely Benign | -0.32 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.17 | Pathogenic | 0.54 | Tolerated | 0.2380 | 0.3885 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.849G>C | E283D 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant E283D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: benign predictions come from REVEL and SIFT, whereas pathogenic predictions are made by AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and FoldX. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts a pathogenic change, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic. The Foldetta stability analysis is inconclusive and therefore treated as unavailable. Overall, the majority of evidence points to a pathogenic effect for E283D, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.098513 | Structured | 0.358602 | Uncertain | 0.950 | 0.249 | 0.000 | -10.190 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.25 | Destabilizing | 0.2 | 0.94 | Ambiguous | 1.60 | Ambiguous | 0.60 | Ambiguous | 0.280 | Likely Benign | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.63 | Pathogenic | 0.06 | Tolerated | 0.2008 | 0.3480 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.849G>T | E283D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E283D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL and SIFT, whereas a majority of tools predict a pathogenic impact: AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and FoldX. Predictions that remain inconclusive are Foldetta, Rosetta, and premPS. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta’s stability analysis is uncertain. Overall, the preponderance of evidence indicates that E283D 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 | 0.098513 | Structured | 0.358602 | Uncertain | 0.950 | 0.249 | 0.000 | -10.190 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.25 | Destabilizing | 0.2 | 0.94 | Ambiguous | 1.60 | Ambiguous | 0.60 | Ambiguous | 0.280 | Likely Benign | -2.76 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.63 | Pathogenic | 0.06 | Tolerated | 0.2008 | 0.3480 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.850C>A | L284I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L284I missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, 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 FATHMM. 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 uncertain. No evidence from FoldX or Rosetta alone is conclusive. Overall, the majority of predictions, including the high‑accuracy methods, support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.094817 | Structured | 0.371601 | Uncertain | 0.950 | 0.255 | 0.000 | -5.853 | Likely Benign | 0.293 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.0 | 1.22 | Ambiguous | 0.86 | Ambiguous | 0.49 | Likely Benign | 0.364 | Likely Benign | -1.51 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.88 | Pathogenic | 0.13 | Tolerated | 0.0738 | 0.3006 | 2 | 2 | 0.7 | 0.00 | |||||||||||||||||||||||||||||
| c.853T>A | C285S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285S has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas a majority of the remaining predictors (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default) indicate a pathogenic impact. The remaining tools (FoldX, Rosetta, Foldetta, ESM1b, AlphaMissense‑Optimized) return uncertain results, which are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.149 | In-Between | 0.868 | Likely Pathogenic | Ambiguous | 0.73 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.74 | Ambiguous | 1.20 | Destabilizing | 0.507 | Likely Pathogenic | -8.09 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.90 | Pathogenic | 0.08 | Tolerated | 0.5210 | 0.2038 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| c.854G>A | C285Y 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285Y is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and Rosetta. Those that agree on a pathogenic effect include SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Predictions that are inconclusive are Foldetta, premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points to a pathogenic impact for C285Y. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.210 | In-Between | 0.895 | Likely Pathogenic | Ambiguous | 3.66 | Destabilizing | 1.1 | -2.33 | Stabilizing | 0.67 | Ambiguous | 0.53 | Ambiguous | 0.484 | Likely Benign | -8.67 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.18 | Tolerated | 0.1413 | 0.3689 | 0 | -2 | -3.8 | 60.04 | |||||||||||||||||||||||||||||
| c.854G>C | C285S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285S is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and SIFT, whereas premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default all predict a pathogenic outcome. Predictions from FoldX, Rosetta, ESM1b, AlphaMissense‑Optimized, and Foldetta are inconclusive. High‑accuracy methods give the following results: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for C285S, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -7.149 | In-Between | 0.868 | Likely Pathogenic | Ambiguous | 0.73 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.74 | Ambiguous | 1.20 | Destabilizing | 0.499 | Likely Benign | -8.09 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.90 | Pathogenic | 0.08 | Tolerated | 0.5210 | 0.2038 | Weaken | 0 | -1 | -3.3 | -16.06 | ||||||||||||||||||||||||||||
| c.854G>T | C285F 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant C285F is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome; Foldetta is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence (12 pathogenic vs. 3 benign predictions) indicates that the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -9.397 | Likely Pathogenic | 0.716 | Likely Pathogenic | Likely Benign | 3.27 | Destabilizing | 1.1 | -1.72 | Ambiguous | 0.78 | Ambiguous | 0.35 | Likely Benign | 0.500 | Likely Pathogenic | -8.84 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 1.81 | Pathogenic | 0.12 | Tolerated | 0.1626 | 0.4007 | -4 | -2 | 0.3 | 44.04 | |||||||||||||||||||||||||||||
| c.855C>G | C285W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant C285W is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and Rosetta, whereas pathogenic predictions are made by SGM‑Consensus, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy subset confirms this trend: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenicity, and Foldetta remains uncertain. No prediction tool is missing or inconclusive enough to alter the overall assessment. 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 | C2 | 0.144935 | Structured | 0.375400 | Uncertain | 0.946 | 0.250 | 0.000 | -9.017 | Likely Pathogenic | 0.969 | Likely Pathogenic | Likely Pathogenic | 3.35 | Destabilizing | 1.1 | -2.28 | Stabilizing | 0.54 | Ambiguous | 0.61 | Ambiguous | 0.327 | Likely Benign | -8.97 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.78 | Pathogenic | 0.11 | Tolerated | 0.1934 | 0.3697 | -8 | -2 | -3.4 | 83.07 | |||||||||||||||||||||||||||||
| c.859G>A | D287N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D287N missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions (REVEL, FoldX, premPS, SIFT) and pathogenic predictions (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default). Two tools give uncertain results (Rosetta, AlphaMissense‑Optimized). High‑accuracy assessments further separate the evidence: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic effect; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign impact. Overall, the majority of conventional predictors lean toward pathogenicity, while the most accurate stability‑based method suggests benign. Thus, the variant is most likely pathogenic based on the prevailing predictions, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -10.167 | Likely Pathogenic | 0.944 | Likely Pathogenic | Ambiguous | 0.16 | Likely Benign | 0.3 | -0.54 | Ambiguous | -0.19 | Likely Benign | 0.05 | Likely Benign | 0.372 | Likely Benign | -4.60 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.62 | Pathogenic | 0.06 | Tolerated | 0.1338 | 0.8194 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.863A>C | D288A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288A missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, and SIFT. Those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. AlphaMissense‑Optimized, Foldetta, and Rosetta give uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show that the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenicity, AlphaMissense‑Optimized is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. Overall, seven tools predict pathogenicity while four predict benign, with no conflicting ClinVar evidence. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -13.470 | Likely Pathogenic | 0.908 | Likely Pathogenic | Ambiguous | 0.34 | Likely Benign | 0.1 | 1.27 | Ambiguous | 0.81 | Ambiguous | 0.10 | Likely Benign | 0.451 | Likely Benign | -6.09 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.71 | Pathogenic | 0.07 | Tolerated | 0.4060 | 0.5788 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.863A>G | D288G 2D 3DClick to see structure in 3D Viewer AISynGAP1 D288G is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, AlphaMissense‑Optimized, and Foldetta. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. No folding‑stability result is available from FoldX. Overall, the balance of evidence slightly favors a pathogenic interpretation, with one high‑accuracy tool supporting benignity. The prediction does not contradict ClinVar status, as the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -8.531 | Likely Pathogenic | 0.739 | Likely Pathogenic | Likely Benign | -0.71 | Ambiguous | 0.4 | 0.21 | Likely Benign | -0.25 | Likely Benign | -0.15 | Likely Benign | 0.436 | Likely Benign | -5.03 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.05 | Pathogenic | 0.13 | Tolerated | 0.4126 | 0.5934 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.864C>A | D288E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -6.685 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.42 | Likely Benign | -0.10 | Likely Benign | 0.203 | Likely Benign | -2.84 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.74 | Pathogenic | 0.13 | Tolerated | 0.1559 | 0.5476 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.864C>G | D288E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D288E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Two tools give uncertain results: Rosetta and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.125101 | Structured | 0.395525 | Uncertain | 0.873 | 0.261 | 0.000 | -6.685 | Likely Benign | 0.350 | Ambiguous | Likely Benign | 0.10 | Likely Benign | 0.0 | 0.74 | Ambiguous | 0.42 | Likely Benign | -0.10 | Likely Benign | 0.203 | Likely Benign | -2.84 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.74 | Pathogenic | 0.13 | Tolerated | 0.1559 | 0.5476 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.865A>C | M289L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289L 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, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a “Likely Benign” verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also reports a benign effect. No prediction or 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 available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -5.778 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.0 | -0.10 | Likely Benign | 0.02 | Likely Benign | 0.39 | Likely Benign | 0.070 | Likely Benign | -0.95 | Neutral | 0.136 | Benign | 0.033 | Benign | 1.79 | Pathogenic | 0.27 | Tolerated | 0.1092 | 0.3634 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.865A>G | M289V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant M289V is reported in ClinVar as Benign (ClinVar ID 2122760.0) and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus all predict benign, while only FATHMM predicts pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates benign. No prediction or stability result is inconclusive. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | Benign | 1 | -4.239 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 1.09 | Ambiguous | 0.1 | -0.27 | Likely Benign | 0.41 | Likely Benign | 0.24 | Likely Benign | 0.150 | Likely Benign | -0.36 | Neutral | 0.136 | Benign | 0.054 | Benign | 1.80 | Pathogenic | 1.00 | Tolerated | 3.38 | 23 | 0.2280 | 0.2808 | 2 | 1 | 2.3 | -32.06 | 204.2 | 51.0 | 0.0 | 0.0 | 0.2 | 0.0 | X | Potentially Benign | The hydrophobic residue Met289, located in a β hairpin linking two anti-parallel β sheet strands (res. Met289-Arg299, res. Arg272-Leu286), is swapped for another hydrophobic residue, valine. In the variant simulations, the branched hydrocarbon side chain of Val289 packs against the phenol group of the Tyr291 side chain but is unable to form methionine-aromatic interactions. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. However, based on the simulations, the residue swap does not cause adverse effects on the structure. | ||||||||||||||||
| c.865A>T | M289L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is benign. No prediction or folding stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not currently listed in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -5.778 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.0 | -0.10 | Likely Benign | 0.02 | Likely Benign | 0.39 | Likely Benign | 0.070 | Likely Benign | -0.95 | Neutral | 0.136 | Benign | 0.033 | Benign | 1.79 | Pathogenic | 0.27 | Tolerated | 0.1092 | 0.3634 | 4 | 2 | 1.9 | -18.03 | |||||||||||||||||||||||||||||
| c.866T>A | M289K 2D  3DClick to see structure in 3D Viewer AISynGAP1 M289K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely pathogenic classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Because the majority of consensus and individual predictors lean toward pathogenicity, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status since none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -12.192 | Likely Pathogenic | 0.738 | Likely Pathogenic | Likely Benign | 0.36 | Likely Benign | 0.2 | 0.60 | Ambiguous | 0.48 | Likely Benign | 0.94 | Ambiguous | 0.229 | Likely Benign | -2.52 | Deleterious | 0.891 | Possibly Damaging | 0.492 | Possibly Damaging | 1.94 | Pathogenic | 0.12 | Tolerated | 0.1271 | 0.0879 | 0 | -1 | -5.8 | -3.02 | |||||||||||||||||||||||||||||
| c.866T>C | M289T 2D AIThe SynGAP1 missense variant M289T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools that classify the variant as benign include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts a benign effect. Taken together, the majority of evidence indicates that M289T is most likely benign, and this conclusion 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 Benign | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | Uncertain | 1 | -4.668 | Likely Benign | 0.238 | Likely Benign | Likely Benign | 0.73 | Ambiguous | 0.1 | 0.17 | Likely Benign | 0.45 | Likely Benign | -0.01 | Likely Benign | 0.222 | Likely Benign | -0.47 | Neutral | 0.801 | Possibly Damaging | 0.315 | Benign | 1.83 | Pathogenic | 0.57 | Tolerated | 0.1657 | 0.1534 | -1 | -1 | -2.6 | -30.09 | |||||||||||||||||||||||||||
| c.866T>G | M289R 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289R has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, Foldetta, SIFT, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions or stability results are missing or inconclusive. Overall, the majority of tools lean toward a pathogenic effect, 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 | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -11.090 | Likely Pathogenic | 0.719 | Likely Pathogenic | Likely Benign | 0.04 | Likely Benign | 0.1 | 0.28 | Likely Benign | 0.16 | Likely Benign | 1.01 | Destabilizing | 0.228 | Likely Benign | -2.84 | Deleterious | 0.989 | Probably Damaging | 0.767 | Possibly Damaging | 1.84 | Pathogenic | 0.08 | Tolerated | 0.1482 | 0.0828 | 0 | -1 | -6.4 | 24.99 | |||||||||||||||||||||||||||||
| c.867G>A | M289I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign prediction; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that M289I is most likely benign, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -6.010 | Likely Benign | 0.505 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.20 | Likely Benign | 0.36 | Likely Benign | 0.040 | Likely Benign | -0.72 | Neutral | 0.005 | Benign | 0.018 | Benign | 1.78 | Pathogenic | 0.31 | Tolerated | 0.1001 | 0.2758 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.867G>C | M289I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that M289I 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. | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -6.010 | Likely Benign | 0.505 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.20 | Likely Benign | 0.36 | Likely Benign | 0.040 | Likely Benign | -0.72 | Neutral | 0.005 | Benign | 0.018 | Benign | 1.78 | Pathogenic | 0.31 | Tolerated | 0.1001 | 0.2758 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.867G>T | M289I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant M289I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and AlphaMissense‑Default are uncertain. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Overall, the preponderance of evidence indicates that M289I 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. | C2 | 0.127496 | Structured | 0.403499 | Uncertain | 0.886 | 0.276 | 0.000 | -6.010 | Likely Benign | 0.505 | Ambiguous | Likely Benign | 0.62 | Ambiguous | 0.1 | -0.23 | Likely Benign | 0.20 | Likely Benign | 0.36 | Likely Benign | 0.040 | Likely Benign | -0.72 | Neutral | 0.005 | Benign | 0.018 | Benign | 1.78 | Pathogenic | 0.31 | Tolerated | 0.1001 | 0.2758 | 2 | 1 | 2.6 | -18.03 | ||||||||||||||||||||||||||||||
| c.869T>A | L290Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L290Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only SIFT, whereas the majority of tools predict a pathogenic impact: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which itself is “Likely Pathogenic”). Uncertain or inconclusive results come from FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus is likely pathogenic, and Foldetta’s stability prediction is unavailable. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.127496 | Structured | 0.399723 | Uncertain | 0.904 | 0.255 | 0.000 | -12.776 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 1.12 | Ambiguous | 0.1 | 1.38 | Ambiguous | 1.25 | Ambiguous | 0.68 | Ambiguous | 0.697 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.97 | Pathogenic | 0.06 | Tolerated | 0.1079 | 0.1014 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.872A>T | Y291F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y291F is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all predict a neutral impact. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict a pathogenic effect, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the majority of evidence supports a benign classification, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.173081 | Structured | 0.383842 | Uncertain | 0.912 | 0.251 | 0.000 | -4.095 | Likely Benign | 0.305 | Likely Benign | Likely Benign | -0.43 | Likely Benign | 0.1 | -0.10 | Likely Benign | -0.27 | Likely Benign | 0.71 | Ambiguous | 0.148 | Likely Benign | -2.31 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.77 | Pathogenic | 0.27 | Tolerated | 0.2362 | 0.3441 | 7 | 3 | 4.1 | -16.00 | |||||||||||||||||||||||||||||
| c.875C>G | A292G 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant A292G is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, whereas the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain, and individual FoldX and Rosetta predictions are also inconclusive. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.247041 | Structured | 0.362042 | Uncertain | 0.929 | 0.256 | 0.000 | -9.692 | Likely Pathogenic | 0.713 | Likely Pathogenic | Likely Benign | 0.88 | Ambiguous | 0.1 | 1.83 | Ambiguous | 1.36 | Ambiguous | 1.05 | Destabilizing | 0.323 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.74 | Pathogenic | 0.10 | Tolerated | 0.2187 | 0.5054 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.883A>G | T295A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295A missense variant has no ClinVar entry and is not reported in gnomAD. Prediction tools cluster into benign (REVEL, FoldX, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). Four tools are uncertain (Rosetta, Foldetta, premPS, ESM1b). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as inconclusive. Overall, the majority of conventional predictors lean toward a benign effect, whereas the SGM Consensus indicates a pathogenic signal. Thus, the variant is most likely benign based on the bulk of evidence, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -7.276 | In-Between | 0.336 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | 1.17 | Ambiguous | 0.70 | Ambiguous | 0.56 | Ambiguous | 0.340 | Likely Benign | -3.51 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.96 | Pathogenic | 0.11 | Tolerated | 0.4623 | 0.4190 | 1 | 0 | 2.5 | -30.03 | ||||||||||||||||||||||||||||||
| c.883A>T | T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -4.904 | Likely Benign | 0.335 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.2 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.54 | Ambiguous | 0.218 | Likely Benign | -2.16 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.14 | Tolerated | 0.3910 | 0.4473 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.884C>G | T295S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T295S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; premPS is inconclusive. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority (3 benign vs. 1 pathogenic); and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -4.904 | Likely Benign | 0.335 | Likely Benign | Likely Benign | -0.16 | Likely Benign | 0.2 | 0.28 | Likely Benign | 0.06 | Likely Benign | 0.54 | Ambiguous | 0.196 | Likely Benign | -2.16 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.14 | Tolerated | 0.3910 | 0.4473 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.886T>A | S296T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 S296T missense variant is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors shows a split: six tools (REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT) and AlphaMissense‑Optimized predict a benign effect, whereas four tools (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default) predict pathogenicity. ESM1b remains uncertain. High‑accuracy assessments give a more definitive picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans toward pathogenicity, and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a benign outcome. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -7.020 | In-Between | 0.645 | Likely Pathogenic | Likely Benign | 0.09 | Likely Benign | 0.4 | 0.38 | Likely Benign | 0.24 | Likely Benign | 0.19 | Likely Benign | 0.201 | Likely Benign | -2.10 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.13 | Pathogenic | 0.13 | Tolerated | 0.1437 | 0.6340 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.886T>C | S296P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, Rosetta, and SIFT, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. When predictions are grouped by agreement, four tools predict benign and seven predict pathogenic, with premPS remaining uncertain. High‑accuracy methods give a mixed signal: AlphaMissense‑Optimized predicts pathogenic; the SGM‑Consensus, derived from the unanimous pathogenic vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a benign effect. Thus, the majority of evidence leans toward pathogenicity, and this conclusion is consistent with the lack of ClinVar annotation and gnomAD absence, which do not contradict the prediction. Overall, the variant is most likely pathogenic based on the current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | -8.302 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.04 | Likely Benign | 0.4 | 0.18 | Likely Benign | 0.11 | Likely Benign | 0.72 | Ambiguous | 0.439 | Likely Benign | -3.74 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.92 | Pathogenic | 0.12 | Tolerated | 0.2273 | 0.6320 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.886T>G | S296A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S296A (ClinVar ID 469166.0) is listed as ClinVar status Uncertain and is not present in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign or neutral. In contrast, polyPhen‑2 (HumDiv and HumVar) and FATHMM predict pathogenic. Grouping by consensus, the benign‑predicting tools outnumber the pathogenic ones. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is also benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports a benign effect. No evidence from the available tools suggests a deleterious impact. Therefore, the variant is most likely benign, and this conclusion is consistent with its ClinVar status of Uncertain rather than pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.444081 | Structured | 0.282669 | Uncertain | 0.887 | 0.284 | 0.250 | Uncertain | 1 | -6.847 | Likely Benign | 0.247 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.3 | -0.26 | Likely Benign | 0.12 | Likely Benign | 0.35 | Likely Benign | 0.209 | Likely Benign | -1.79 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.97 | Pathogenic | 0.65 | Tolerated | 3.40 | 16 | 0.4958 | 0.5522 | 1 | 1 | 2.6 | -16.00 | 182.5 | 26.6 | -0.2 | 0.1 | -0.5 | 0.0 | X | Potentially Pathogenic | The hydroxyl group of the Ser296 side chain, located in an anti-parallel β sheet strand (res. Met289-Pro298), stably hydrogen bonds with the carboxylate group of Asp330 in a neighboring β strand (res. Ala322-Asp332). The backbone carbonyl group of Ser296 also hydrogen bonds with the guanidinium group of Arg279 in another nearby β strand (res. Arg279-Cys285). In the variant simulations, the methyl group of the Ala296 side chain cannot hydrogen bond with Asp330, causing the carboxylate group positioning to fluctuate more than in the WT simulations.Although the residue swap does not seem to affect the anti-parallel β sheet assembly during the simulations, it is possible that the Ser296-Asp330 hydrogen bond plays a crucial role in maintaining the C2 domain fold. Notably, because Ser296 is located near the membrane interface, the potential effect of the residue swap on the SynGAP-membrane association cannot be addressed by solvent-only simulations. | ||||||||||||||||
| c.890A>G | K297R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K297R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Foldetta, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. Predictions that are uncertain or inconclusive are FoldX, Rosetta, premPS, and ESM1b. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign; and Foldetta, a protein‑folding stability approach combining FoldX‑MD and Rosetta, predicts benign. Based on the aggregate of these predictions, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.422041 | Structured | 0.272593 | Uncertain | 0.880 | 0.285 | 0.375 | -7.877 | In-Between | 0.314 | Likely Benign | Likely Benign | -0.86 | Ambiguous | 0.3 | 0.67 | Ambiguous | -0.10 | Likely Benign | 0.66 | Ambiguous | 0.257 | Likely Benign | -2.36 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.66 | Pathogenic | 0.19 | Tolerated | 0.4828 | 0.1506 | 3 | 2 | -0.6 | 28.01 | ||||||||||||||||||||||||||||||
| c.892C>A | P298T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain results and are treated as unavailable for pathogenicity inference. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a benign prediction, while Foldetta remains uncertain. Overall, the preponderance of evidence points to a benign effect for P298T, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -7.366 | In-Between | 0.104 | Likely Benign | Likely Benign | 1.44 | Ambiguous | 0.2 | 1.03 | Ambiguous | 1.24 | Ambiguous | 0.04 | Likely Benign | 0.209 | Likely Benign | -0.13 | Neutral | 0.939 | Possibly Damaging | 0.739 | Possibly Damaging | 1.96 | Pathogenic | 1.00 | Tolerated | 0.1595 | 0.6349 | 0 | -1 | 0.9 | 3.99 | ||||||||||||||||||||||||||||||
| c.892C>G | P298A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No evidence from FoldX or Rosetta alone is conclusive. Based on the preponderance of benign predictions and the lack of pathogenic consensus, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -6.082 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 1.22 | Ambiguous | 0.1 | 1.17 | Ambiguous | 1.20 | Ambiguous | 0.50 | Likely Benign | 0.191 | Likely Benign | -0.98 | Neutral | 0.885 | Possibly Damaging | 0.589 | Possibly Damaging | 1.94 | Pathogenic | 0.66 | Tolerated | 0.3761 | 0.5787 | 1 | -1 | 3.4 | -26.04 | |||||||||||||||||||||||||||||
| c.892C>T | P298S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298S is listed in ClinVar as Benign (ClinVar ID 2965590.0) and is present in gnomAD (ID 6‑33437797‑C‑T). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Uncertain. No evidence from FoldX, Rosetta, or premPS is available to support either outcome. Overall, the majority of predictions support a benign impact, aligning with the ClinVar designation. Thus, the variant is most likely benign and does not contradict the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | Benign | 1 | 6-33437797-C-T | 5 | 3.10e-6 | -6.342 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 1.38 | Ambiguous | 0.2 | 1.41 | Ambiguous | 1.40 | Ambiguous | 0.58 | Ambiguous | 0.189 | Likely Benign | -1.20 | Neutral | 0.991 | Probably Damaging | 0.898 | Possibly Damaging | 2.03 | Pathogenic | 0.85 | Tolerated | 3.39 | 20 | 0.3678 | 0.5855 | -1 | 1 | 0.8 | -10.04 | ||||||||||||||||||||||
| c.893C>G | P298R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant P298R has no ClinVar entry and is not reported in gnomAD. Computational predictors fall into two consensus groups: benign predictions come from REVEL, FoldX, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from SGM‑Consensus, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported only by Foldetta and premPS. High‑accuracy tools give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta reports an uncertain stability change. Overall, the majority of evidence points toward a pathogenic effect, and this assessment is not contradicted by ClinVar, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -11.427 | Likely Pathogenic | 0.733 | Likely Pathogenic | Likely Benign | 0.45 | Likely Benign | 0.0 | 2.08 | Destabilizing | 1.27 | Ambiguous | 0.61 | Ambiguous | 0.280 | Likely Benign | -1.83 | Neutral | 0.997 | Probably Damaging | 0.952 | Probably Damaging | 2.03 | Pathogenic | 0.09 | Tolerated | 0.1299 | 0.3872 | 0 | -2 | -2.9 | 59.07 | |||||||||||||||||||||||||||||
| c.893C>T | P298L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 P298L missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign outcome; and Foldetta’s stability prediction is unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.328603 | Structured | 0.268765 | Uncertain | 0.860 | 0.283 | 0.500 | -7.334 | In-Between | 0.107 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.2 | 1.53 | Ambiguous | 1.07 | Ambiguous | -0.16 | Likely Benign | 0.267 | Likely Benign | -0.82 | Neutral | 0.885 | Possibly Damaging | 0.589 | Possibly Damaging | 1.91 | Pathogenic | 0.21 | Tolerated | 0.2137 | 0.6795 | -3 | -3 | 5.4 | 16.04 | ||||||||||||||||||||||||||||||
| c.895C>A | R299S 2D 3DClick to see structure in 3D Viewer AISynGAP1 R299S is not reported in ClinVar and is absent from gnomAD. Among in‑silico predictors, benign calls come from REVEL and SIFT, while pathogenic calls are made by FoldX, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by Rosetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy methods give a pathogenic verdict: AlphaMissense‑Optimized is inconclusive, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) also predicts pathogenic. Overall, the evidence points to a pathogenic effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | -7.276 | In-Between | 0.882 | Likely Pathogenic | Ambiguous | 2.86 | Destabilizing | 0.3 | 1.46 | Ambiguous | 2.16 | Destabilizing | 1.07 | Destabilizing | 0.241 | Likely Benign | -3.20 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.75 | Pathogenic | 0.07 | Tolerated | 0.2780 | 0.5057 | 0 | -1 | 3.7 | -69.11 | |||||||||||||||||||||||||||||
| c.895C>T | R299C 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R299C is listed in ClinVar with an uncertain significance (ClinVar ID 1335623.0) and is present in gnomAD (ID 6‑33437800‑C‑T). Prediction tools that classify the variant as benign include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Other stability predictors (FoldX, Rosetta, premPS) are also uncertain. Overall, the balance of evidence favors a pathogenic interpretation, which does not contradict the ClinVar uncertain status but suggests a higher likelihood of disease relevance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.321458 | Structured | 0.262979 | Uncertain | 0.819 | 0.295 | 0.500 | Conflicting | 2 | 6-33437800-C-T | 3 | 1.86e-6 | -6.326 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 1.85 | Ambiguous | 0.4 | 0.61 | Ambiguous | 1.23 | Ambiguous | 0.76 | Ambiguous | 0.344 | Likely Benign | -3.54 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.65 | Pathogenic | 0.06 | Tolerated | 3.39 | 19 | 0.3035 | 0.4564 | -4 | -3 | 7.0 | -53.05 | 210.7 | 91.3 | 0.1 | 0.0 | 0.0 | 0.2 | X | X | Potentially Pathogenic | The guanidinium group of Arg299, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), forms hydrogen bonds that stabilize the tight turn. In the WT simulations, the Arg299 side chain hydrogen bonds with the loop backbone carbonyl groups (e.g., Ser302, Thr305, Leu274, Gly303), the hydroxyl group of Ser300, and even forms a salt bridge with the carboxylate group of Asp304.In the variant simulations, the thiol group of the Cys299 side chain is unable to form any of these well-coordinated or strong interactions, which could affect the initial formation of the secondary hairpin loop during folding. β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Moreover, the positively charged Arg299 side chain faces the polar head group region of the inner leaflet membrane and could directly anchor the C2 domain to the membrane. In short, the residue swap could negatively affect both protein folding and the stability of the SynGAP-membrane association. | ||||||||||||
| c.898T>A | S300T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM indicates a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, and this conclusion does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -4.648 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.1 | -0.30 | Likely Benign | 0.28 | Likely Benign | -0.33 | Likely Benign | 0.056 | Likely Benign | 0.50 | Neutral | 0.003 | Benign | 0.002 | Benign | 1.94 | Pathogenic | 0.85 | Tolerated | 0.1409 | 0.6428 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.898T>G | S300A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Rosetta and Foldetta give uncertain results and are therefore not considered evidence for either side. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also benign (3 benign vs. 1 pathogenic). Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -5.420 | Likely Benign | 0.060 | Likely Benign | Likely Benign | 0.08 | Likely Benign | 0.3 | 1.07 | Ambiguous | 0.58 | Ambiguous | 0.08 | Likely Benign | 0.031 | Likely Benign | -1.18 | Neutral | 0.139 | Benign | 0.060 | Benign | 1.56 | Pathogenic | 0.20 | Tolerated | 0.5135 | 0.4949 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.901G>A | A301T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301T is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437806‑G‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is benign. Overall, the majority of evidence points to a benign effect, and this is not in conflict with the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | Uncertain | 5 | 6-33437806-G-A | 2 | 1.24e-6 | -3.448 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.2 | -0.33 | Likely Benign | 0.02 | Likely Benign | 0.03 | Likely Benign | 0.150 | Likely Benign | -0.25 | Neutral | 0.997 | Probably Damaging | 0.989 | Probably Damaging | 4.15 | Benign | 0.22 | Tolerated | 4.32 | 14 | 0.1362 | 0.7201 | 1 | 0 | -2.5 | 30.03 | 219.8 | -42.8 | -0.1 | 0.0 | -0.5 | 0.2 | Uncertain | The methyl group of Ala301, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Met289-Pro298, res. Thr305-Asn315), points outward from the β hairpin loop, and its backbone atoms do not participate in the loop formation in the WT simulations. In the variant simulations, the hydroxyl group of the Thr301 side chain also mostly points outward; however, the guanidinium group of Arg299 is moved away from its central hairpin loop position.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | ||||||||||||||
| c.901G>C | A301P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools—polyPhen‑2 HumDiv and polyPhen‑2 HumVar—predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -3.808 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.47 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.44 | Likely Benign | 0.40 | Likely Benign | 0.225 | Likely Benign | -0.83 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.11 | Benign | 0.06 | Tolerated | 0.1907 | 0.5371 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.901G>T | A301S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301S is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly indicate a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy methods corroborate the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. No evidence from these analyses suggests a deleterious effect. Therefore, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -2.488 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.1 | -0.32 | Likely Benign | -0.06 | Likely Benign | 0.22 | Likely Benign | 0.151 | Likely Benign | -0.28 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 4.21 | Benign | 0.13 | Tolerated | 0.2706 | 0.6022 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.902C>A | A301D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301D is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM all predict benign, whereas polyPhen‑2 (HumDiv and HumVar) and ESM1b predict pathogenic. Tools with uncertain outputs—Rosetta, Foldetta, and AlphaMissense‑Default—do not provide decisive evidence. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized classifies the variant as benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also yields a benign verdict; Foldetta remains inconclusive. Taken together, the preponderance of evidence indicates that A301D is most likely benign, and this assessment does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -10.276 | Likely Pathogenic | 0.488 | Ambiguous | Likely Benign | -0.37 | Likely Benign | 0.2 | -1.15 | Ambiguous | -0.76 | Ambiguous | 0.23 | Likely Benign | 0.224 | Likely Benign | -0.35 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.17 | Benign | 0.07 | Tolerated | 0.1599 | 0.1705 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||
| c.902C>G | A301G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301G is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, classifies the variant as Benign. Overall, the consensus of the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar claim. Therefore, the variant is most likely benign, and this is not contradictory to ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -3.085 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.27 | Likely Benign | 0.1 | 0.34 | Likely Benign | 0.31 | Likely Benign | 0.37 | Likely Benign | 0.128 | Likely Benign | -0.37 | Neutral | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 4.18 | Benign | 0.28 | Tolerated | 0.2425 | 0.5054 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.902C>T | A301V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A301V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Thus, the overall evidence supports a benign classification for A301V, and this conclusion is consistent with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.429200 | Structured | 0.258424 | Uncertain | 0.647 | 0.272 | 0.375 | -2.476 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.25 | Likely Benign | 0.1 | 0.48 | Likely Benign | 0.37 | Likely Benign | 0.06 | Likely Benign | 0.116 | Likely Benign | -0.49 | Neutral | 0.997 | Probably Damaging | 0.983 | Probably Damaging | 4.14 | Benign | 0.26 | Tolerated | 0.1096 | 0.6264 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.904T>A | S302T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302T is not reported in ClinVar and is absent from gnomAD. All available in silico predictors classify the substitution as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). No tool predicts pathogenicity. High‑accuracy assessments concur: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -4.742 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.1 | 0.10 | Likely Benign | 0.15 | Likely Benign | -0.08 | Likely Benign | 0.043 | Likely Benign | -0.55 | Neutral | 0.037 | Benign | 0.042 | Benign | 4.16 | Benign | 0.15 | Tolerated | 0.1715 | 0.6886 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.904T>C | S302P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S302P is not reported in ClinVar and is absent from gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only Rosetta predicts a pathogenic outcome, while FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM‑Consensus, derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also supports a benign classification. Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains inconclusive. Overall, the preponderance of evidence points to a benign impact for S302P, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -2.485 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 1.19 | Ambiguous | 0.4 | 2.74 | Destabilizing | 1.97 | Ambiguous | 0.14 | Likely Benign | 0.101 | Likely Benign | -0.89 | Neutral | 0.157 | Benign | 0.153 | Benign | 4.11 | Benign | 0.20 | Tolerated | 0.2522 | 0.6243 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.904T>G | S302A 2D AIThe SynGAP1 missense variant S302A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not currently catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.263489 | Uncertain | 0.616 | 0.258 | 0.375 | -2.583 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.21 | Likely Benign | 0.4 | 0.65 | Ambiguous | 0.43 | Likely Benign | 0.02 | Likely Benign | 0.044 | Likely Benign | -0.41 | Neutral | 0.000 | Benign | 0.001 | Benign | 4.16 | Benign | 0.20 | Tolerated | 0.5358 | 0.5407 | Strenghten | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.907G>A | G303R 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G303R is catalogued in gnomAD (6-33437812-G-A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome; the remaining tools (FoldX, Foldetta, premPS, ESM1b) are inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, while Foldetta remains uncertain. Taken together, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | 6-33437812-G-A | 1 | 6.20e-7 | -7.493 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 1.44 | Ambiguous | 0.4 | 0.23 | Likely Benign | 0.84 | Ambiguous | 0.73 | Ambiguous | 0.048 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.99 | Benign | 0.06 | Tolerated | 3.55 | 18 | 0.0839 | 0.4490 | -2 | -3 | -4.1 | 99.14 | |||||||||||||||||||||||||
| c.907G>C | G303R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome. The remaining tools—FoldX, Foldetta, premPS, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign, while Foldetta remains uncertain. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -7.493 | In-Between | 0.724 | Likely Pathogenic | Likely Benign | 1.44 | Ambiguous | 0.4 | 0.23 | Likely Benign | 0.84 | Ambiguous | 0.73 | Ambiguous | 0.048 | Likely Benign | -1.38 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.99 | Benign | 0.06 | Tolerated | 3.55 | 18 | 0.0839 | 0.4490 | -2 | -3 | -4.1 | 99.14 | ||||||||||||||||||||||||||||
| c.908G>C | G303A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G303A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Rosetta, and Foldetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts benign, while Foldetta’s stability analysis is uncertain. Overall, the variant is most likely benign based on the consensus of predictive tools, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.450668 | Structured | 0.271087 | Uncertain | 0.630 | 0.254 | 0.250 | -1.965 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 1.66 | Ambiguous | 0.2 | -0.51 | Ambiguous | 0.58 | Ambiguous | 0.10 | Likely Benign | 0.034 | Likely Benign | -0.90 | Neutral | 0.112 | Benign | 0.058 | Benign | 4.07 | Benign | 0.35 | Tolerated | 0.3724 | 0.5325 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.913A>C | T305P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305P missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as pathogenic, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of tools (7 pathogenic vs. 5 benign) lean toward a pathogenic impact, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -5.203 | Likely Benign | 0.177 | Likely Benign | Likely Benign | 3.64 | Destabilizing | 1.1 | 6.02 | Destabilizing | 4.83 | Destabilizing | 0.71 | Ambiguous | 0.293 | Likely Benign | -2.83 | Deleterious | 0.997 | Probably Damaging | 0.929 | Probably Damaging | 1.72 | Pathogenic | 0.06 | Tolerated | 0.2206 | 0.5333 | 0 | -1 | -0.9 | -3.99 | ||||||||||||||||||||||||||||||
| c.913A>G | T305A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T305A variant is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437818‑A‑G). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | Conflicting | 2 | 6-33437818-A-G | 13 | 8.05e-6 | -4.307 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 1.30 | Ambiguous | 0.6 | 1.55 | Ambiguous | 1.43 | Ambiguous | 0.77 | Ambiguous | 0.144 | Likely Benign | -2.10 | Neutral | 0.939 | Possibly Damaging | 0.645 | Possibly Damaging | 1.76 | Pathogenic | 0.12 | Tolerated | 3.40 | 20 | 0.4277 | 0.4403 | 1 | 0 | 2.5 | -30.03 | 177.9 | 43.5 | -0.2 | 0.1 | 0.4 | 0.0 | Uncertain | The hydroxyl group of Thr305, located at the beginning of an anti-parallel β strand (res. Thr305-Asn315), hydrogen bonds with the carboxylate groups of Glu270 and Asp304 in the anti-parallel β strand and the adjacent β hairpin loop, respectively. In the variant simulations, the methyl group of the Ala305 side chain cannot hydrogen bond with either of the acidic residues, which could weaken the integrity of the tertiary structure and the β hairpin loop. Indeed, the guanidinium group of Arg299 does not acquire its central hairpin loop position due to the residue swap.β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. Due to its location near the membrane surface, the residue swap could also affect the C2 loop dynamics and SynGAP-membrane association. However, this is beyond the scope of the solvent-only simulations to unravel. | ||||||||||||||
| c.913A>T | T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -2.899 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.4 | 1.21 | Ambiguous | 0.83 | Ambiguous | 0.55 | Ambiguous | 0.135 | Likely Benign | -0.60 | Neutral | 0.760 | Possibly Damaging | 0.484 | Possibly Damaging | 1.86 | Pathogenic | 0.54 | Tolerated | 0.3579 | 0.4496 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.914C>A | T305N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T305N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign, and the SGM‑Consensus score is “Likely Benign.” Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, and the combined Foldetta) return uncertain or inconclusive results. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign, and Foldetta remains uncertain. Overall, the majority of evidence supports a benign impact for T305N, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -3.261 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 1.18 | Ambiguous | 0.2 | 1.65 | Ambiguous | 1.42 | Ambiguous | 0.09 | Likely Benign | 0.098 | Likely Benign | 0.71 | Neutral | 0.046 | Benign | 0.040 | Benign | 2.34 | Pathogenic | 0.67 | Tolerated | 0.1327 | 0.4352 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.914C>G | T305S 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305S is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive or uncertain are provided by Rosetta, Foldetta, and premPS. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates “Likely Benign,” and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | -2.899 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.4 | 1.21 | Ambiguous | 0.83 | Ambiguous | 0.55 | Ambiguous | 0.104 | Likely Benign | -0.60 | Neutral | 0.760 | Possibly Damaging | 0.484 | Possibly Damaging | 1.86 | Pathogenic | 0.54 | Tolerated | 0.3579 | 0.4496 | 1 | 1 | -0.1 | -14.03 | |||||||||||||||||||||||||||||
| c.916G>A | V306I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V306I is not reported in ClinVar (no ClinVar ID) but is present in gnomAD (variant ID 6-33437821‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. No prediction or stability assessment is missing; all available data are considered. Based on the preponderance of benign predictions and the lack of ClinVar evidence to the contrary, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | 6-33437821-G-A | 11 | 6.82e-6 | -5.989 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 1.13 | Ambiguous | 0.2 | 0.38 | Likely Benign | 0.76 | Ambiguous | 0.19 | Likely Benign | 0.154 | Likely Benign | -0.17 | Neutral | 0.999 | Probably Damaging | 0.993 | Probably Damaging | 1.75 | Pathogenic | 0.36 | Tolerated | 3.38 | 19 | 0.0603 | 0.3461 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||
| c.916G>C | V306L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V306L missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta is inconclusive. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | -3.633 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 2.14 | Destabilizing | 0.2 | 1.47 | Ambiguous | 1.81 | Ambiguous | 0.75 | Ambiguous | 0.161 | Likely Benign | -1.01 | Neutral | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.76 | Pathogenic | 0.21 | Tolerated | 0.0823 | 0.4117 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.925G>A | G309S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include REVEL and SIFT, whereas a majority of other in silico predictors (AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SGM‑Consensus, and FoldX) predict it to be pathogenic. Tools with uncertain outcomes (Foldetta, Rosetta, premPS) provide no definitive evidence. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta remains uncertain. Overall, the preponderance of evidence indicates that G309S is most likely pathogenic, and this conclusion does not conflict with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -11.335 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.82 | Destabilizing | 0.5 | 0.73 | Ambiguous | 1.78 | Ambiguous | 0.72 | Ambiguous | 0.487 | Likely Benign | -5.52 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.73 | Pathogenic | 0.07 | Tolerated | 0.2828 | 0.5591 | 1 | 0 | -0.4 | 30.03 | |||||||||||||||||||||||||||||
| c.926G>A | G309D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G309D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions are provided by SIFT and Rosetta, whereas the remaining 12 tools (REVEL, FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus) are pathogenic. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta is inconclusive. Taken together, the majority of evidence supports a pathogenic effect. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -15.264 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.89 | Destabilizing | 0.5 | -0.03 | Likely Benign | 1.43 | Ambiguous | 0.75 | Ambiguous | 0.523 | Likely Pathogenic | -6.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.88 | Pathogenic | 0.06 | Tolerated | 0.1889 | 0.2678 | 1 | -1 | -3.1 | 58.04 | |||||||||||||||||||||||||||||
| c.926G>C | G309A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G309A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and Rosetta, whereas pathogenic calls are made by FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Foldetta, premPS, and ESM1b. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates pathogenic, while Foldetta remains inconclusive. Overall, the preponderance of evidence points to a pathogenic impact for G309A. This conclusion is not contradicted by ClinVar, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.275179 | Structured | 0.338439 | Uncertain | 0.882 | 0.342 | 0.125 | -7.980 | In-Between | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.44 | Destabilizing | 0.4 | 0.30 | Likely Benign | 1.37 | Ambiguous | 0.71 | Ambiguous | 0.373 | Likely Benign | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.69 | Pathogenic | 0.09 | Tolerated | 0.3949 | 0.4974 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.931C>A | H311N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H311N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), and Foldetta as uncertain. Overall, the majority of evaluated tools predict pathogenicity, suggesting that H311N is most likely pathogenic. This prediction does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -9.545 | Likely Pathogenic | 0.661 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.1 | 1.12 | Ambiguous | 0.97 | Ambiguous | 0.72 | Ambiguous | 0.475 | Likely Benign | -5.35 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.89 | Pathogenic | 0.06 | Tolerated | 0.1566 | 0.2380 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.932A>G | H311R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H311R is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, SIFT, and AlphaMissense‑Optimized, whereas a majority of tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) predict a pathogenic outcome. Tools with uncertain or inconclusive results are Rosetta, Foldetta, and premPS. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence favors a pathogenic classification, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.229226 | Structured | 0.354792 | Uncertain | 0.902 | 0.314 | 0.125 | -9.825 | Likely Pathogenic | 0.719 | Likely Pathogenic | Likely Benign | 0.43 | Likely Benign | 0.1 | 0.85 | Ambiguous | 0.64 | Ambiguous | 0.70 | Ambiguous | 0.532 | Likely Pathogenic | -5.72 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.94 | Pathogenic | 0.14 | Tolerated | 0.1931 | 0.2490 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.939G>C | E313D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313D is not 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 SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating a likely pathogenic effect, and Foldetta yielding an uncertain stability change. Overall, the balance of evidence points to a pathogenic interpretation; 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 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -8.309 | Likely Pathogenic | 0.636 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.96 | Ambiguous | 0.92 | Ambiguous | 0.60 | Ambiguous | 0.346 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.88 | Pathogenic | 0.14 | Tolerated | 0.1970 | 0.4640 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.939G>T | E313D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant E313D is not 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 SIFT, whereas a majority of tools predict a pathogenic impact: polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating a likely pathogenic outcome, and Foldetta yielding an uncertain stability change. Overall, the balance of evidence points to a pathogenic effect for E313D, and this conclusion does not contradict the current ClinVar status, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.170161 | Structured | 0.366526 | Uncertain | 0.898 | 0.304 | 0.125 | -8.309 | Likely Pathogenic | 0.636 | Likely Pathogenic | Likely Benign | 0.87 | Ambiguous | 0.0 | 0.96 | Ambiguous | 0.92 | Ambiguous | 0.60 | Ambiguous | 0.346 | Likely Benign | -1.66 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.88 | Pathogenic | 0.14 | Tolerated | 0.1970 | 0.4640 | 3 | 2 | 0.0 | -14.03 | |||||||||||||||||||||||||||||
| c.943A>C | N315H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N315H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign stability. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -6.374 | Likely Benign | 0.156 | Likely Benign | Likely Benign | 0.29 | Likely Benign | 0.2 | 0.22 | Likely Benign | 0.26 | Likely Benign | 0.28 | Likely Benign | 0.258 | Likely Benign | -2.15 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.91 | Pathogenic | 0.76 | Tolerated | 0.1608 | 0.7296 | 2 | 1 | 0.3 | 23.04 | |||||||||||||||||||||||||||||
| c.943A>G | N315D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315D is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and FATHMM. The remaining tools (FoldX, premPS, AlphaMissense‑Default) are inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta predicts a benign stability change. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -5.667 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 1.27 | Ambiguous | 0.6 | -0.30 | Likely Benign | 0.49 | Likely Benign | 0.88 | Ambiguous | 0.229 | Likely Benign | -2.41 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.02 | Pathogenic | 0.45 | Tolerated | 0.1972 | 0.4488 | 2 | 1 | 0.0 | 0.98 | ||||||||||||||||||||||||||||||
| c.943A>T | N315Y 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315Y is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The high‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence slightly favors a pathogenic interpretation, with six pathogenic‑predicted tools versus five benign‑predicted tools, and the high‑accuracy consensus leaning pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -8.303 | Likely Pathogenic | 0.339 | Likely Benign | Likely Benign | -1.03 | Ambiguous | 0.5 | -0.85 | Ambiguous | -0.94 | Ambiguous | -0.10 | Likely Benign | 0.420 | Likely Benign | -3.81 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.93 | Pathogenic | 1.00 | Tolerated | 0.0613 | 0.6732 | -2 | -2 | 2.2 | 49.07 | |||||||||||||||||||||||||||||
| c.944A>C | N315T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Two tools, premPS and ESM1b, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of individual predictors (six benign vs. four pathogenic) and the Foldetta result support a benign classification, while the SGM Consensus suggests pathogenicity. Thus, the variant is most likely benign based on the preponderance of evidence, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -7.071 | In-Between | 0.211 | Likely Benign | Likely Benign | 0.31 | Likely Benign | 0.1 | -0.36 | Likely Benign | -0.03 | Likely Benign | 0.62 | Ambiguous | 0.333 | Likely Benign | -2.91 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.95 | Pathogenic | 0.53 | Tolerated | 0.1471 | 0.8068 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.944A>G | N315S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -4.847 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.2 | 0.78 | Ambiguous | 0.82 | Ambiguous | 0.68 | Ambiguous | 0.250 | Likely Benign | -1.84 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 2.03 | Pathogenic | 0.60 | Tolerated | 0.4022 | 0.7395 | 1 | 1 | 2.7 | -27.03 | |||||||||||||||||||||||||||||
| c.944A>T | N315I 2D  3DClick to see structure in 3D Viewer AISynGAP1 variant N315I is not reported in ClinVar and is absent from gnomAD. In silico predictors that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, and AlphaMissense‑Optimized. Predictors that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD (uncertain) and Rosetta (benign), is considered unavailable. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not conflict with the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -9.666 | Likely Pathogenic | 0.500 | Ambiguous | Likely Benign | -0.72 | Ambiguous | 0.4 | -0.17 | Likely Benign | -0.45 | Likely Benign | 0.36 | Likely Benign | 0.496 | Likely Benign | -5.19 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.90 | Pathogenic | 0.43 | Tolerated | 0.0763 | 0.7235 | -2 | -3 | 8.0 | -0.94 | |||||||||||||||||||||||||||||
| c.945C>A | N315K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315K is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and Foldetta. Tools that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. No other high‑accuracy tool provides a conclusive result. Overall, the majority of predictions (seven pathogenic vs. five benign, with two uncertain) indicate that the variant is most likely pathogenic. This conclusion is not contradicted by ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -10.380 | Likely Pathogenic | 0.872 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.1 | 0.08 | Likely Benign | 0.03 | Likely Benign | 0.87 | Ambiguous | 0.340 | Likely Benign | -3.27 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.98 | Pathogenic | 0.54 | Tolerated | 0.2268 | 0.6436 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.945C>G | N315K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N315K is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and Foldetta. Tools that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is inconclusive, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence (seven pathogenic vs. five benign, with two uncertain) points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.379740 | Uncertain | 0.862 | 0.253 | 0.125 | -10.380 | Likely Pathogenic | 0.872 | Likely Pathogenic | Ambiguous | -0.03 | Likely Benign | 0.1 | 0.08 | Likely Benign | 0.03 | Likely Benign | 0.87 | Ambiguous | 0.340 | Likely Benign | -3.27 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.98 | Pathogenic | 0.54 | Tolerated | 0.2268 | 0.6436 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.946A>G | N316D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316D is not 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, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain and therefore not considered evidence. Overall, seven of the evaluated tools predict pathogenicity versus four predicting benignity, indicating that the variant is most likely pathogenic. This assessment does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -11.672 | Likely Pathogenic | 0.777 | Likely Pathogenic | Likely Benign | 1.18 | Ambiguous | 0.1 | 0.46 | Likely Benign | 0.82 | Ambiguous | 0.69 | Ambiguous | 0.293 | Likely Benign | -3.20 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.76 | Pathogenic | 0.25 | Tolerated | 0.1978 | 0.4596 | 2 | 1 | 0.0 | 0.98 | |||||||||||||||||||||||||||||
| c.947A>C | N316T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Those that agree on a pathogenic effect are FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The remaining tools (AlphaMissense‑Default, ESM1b, Foldetta, premPS, Rosetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta also yields an uncertain stability change. Overall, the majority of available predictions lean toward pathogenicity, and this assessment does not contradict any ClinVar annotation (none is present). 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. | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -7.538 | In-Between | 0.550 | Ambiguous | Likely Benign | 2.71 | Destabilizing | 0.2 | 1.27 | Ambiguous | 1.99 | Ambiguous | 0.57 | Ambiguous | 0.214 | Likely Benign | -3.68 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.79 | Pathogenic | 0.08 | Tolerated | 0.1482 | 0.8474 | 0 | 0 | 2.8 | -13.00 | ||||||||||||||||||||||||||||||
| c.947A>G | N316S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N316S is catalogued in gnomAD (ID 6‑33437852‑A‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Stability‑related methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates Likely Benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with existing clinical annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | 6-33437852-A-G | 1 | 6.20e-7 | -4.512 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 1.19 | Ambiguous | 0.1 | 0.59 | Ambiguous | 0.89 | Ambiguous | 0.68 | Ambiguous | 0.151 | Likely Benign | -2.22 | Neutral | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.77 | Pathogenic | 0.38 | Tolerated | 3.38 | 23 | 0.4333 | 0.7751 | 1 | 1 | 2.7 | -27.03 | ||||||||||||||||||||||||
| c.948C>A | N316K 2D AIThe SynGAP1 missense variant N316K is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include REVEL and SIFT, whereas the majority of tools predict a pathogenic outcome: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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) as uncertain. No other high‑confidence predictions are available. Overall, the preponderance of evidence points to a pathogenic effect for N316K, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -10.711 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.52 | Ambiguous | 0.7 | 0.86 | Ambiguous | 0.69 | Ambiguous | 0.67 | Ambiguous | 0.254 | Likely Benign | -3.87 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.77 | Pathogenic | 0.13 | Tolerated | 0.2220 | 0.6593 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.948C>G | N316K 2D AISynGAP1 missense variant N316K 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 and SIFT, whereas a majority of tools predict pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenicity. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, yields an uncertain result and is treated as unavailable evidence. Overall, the preponderance of computational predictions indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.118441 | Structured | 0.385187 | Uncertain | 0.817 | 0.246 | 0.125 | -10.711 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.52 | Ambiguous | 0.7 | 0.86 | Ambiguous | 0.69 | Ambiguous | 0.67 | Ambiguous | 0.254 | Likely Benign | -3.87 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.77 | Pathogenic | 0.13 | Tolerated | 0.2220 | 0.6593 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.955G>A | A319T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict a pathogenic effect are polyPhen2_HumDiv and FATHMM. The remaining tools—FoldX, Rosetta, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictors classify the variant as 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. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -7.841 | In-Between | 0.098 | Likely Benign | Likely Benign | 0.55 | Ambiguous | 0.3 | 0.70 | Ambiguous | 0.63 | Ambiguous | 0.30 | Likely Benign | 0.116 | Likely Benign | -1.35 | Neutral | 0.775 | Possibly Damaging | 0.306 | Benign | 1.92 | Pathogenic | 0.09 | Tolerated | 0.1274 | 0.6083 | 1 | 0 | -2.5 | 30.03 | ||||||||||||||||||||||||||||||
| c.955G>C | A319P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319P is catalogued in gnomAD (ID 6‑33437860‑G‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Predictions that are inconclusive are Rosetta, ESM1b, and Foldetta. 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 evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | 6-33437860-G-C | 3 | 1.86e-6 | -7.213 | In-Between | 0.109 | Likely Benign | Likely Benign | -0.02 | Likely Benign | 0.9 | -1.18 | Ambiguous | -0.60 | Ambiguous | 0.22 | Likely Benign | 0.286 | Likely Benign | 0.11 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 1.97 | Pathogenic | 1.00 | Tolerated | 3.38 | 23 | 0.1839 | 0.5067 | -1 | 1 | -3.4 | 26.04 | |||||||||||||||||||||||||
| c.955G>T | A319S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as benign. No prediction or 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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -7.109 | In-Between | 0.093 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.09 | Likely Benign | 0.13 | Likely Benign | 0.165 | Likely Benign | -0.58 | Neutral | 0.978 | Probably Damaging | 0.754 | Possibly Damaging | 2.02 | Pathogenic | 0.12 | Tolerated | 0.2537 | 0.4703 | 1 | 1 | -2.6 | 16.00 | ||||||||||||||||||||||||||||||
| c.956C>A | A319D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A319D missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL, FoldX, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a likely pathogenic verdict (3/4 pathogenic votes). High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, whereas the SGM‑Consensus remains pathogenic. Foldetta, which integrates FoldX‑MD (benign) and Rosetta (uncertain), is considered unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not conflict with ClinVar, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -11.144 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | -0.02 | Likely Benign | 0.2 | -0.84 | Ambiguous | -0.43 | Likely Benign | 0.30 | Likely Benign | 0.373 | Likely Benign | -2.38 | Neutral | 0.998 | Probably Damaging | 0.966 | Probably Damaging | 2.01 | Pathogenic | 0.20 | Tolerated | 0.1504 | 0.1360 | 0 | -2 | -5.3 | 44.01 | |||||||||||||||||||||||||||||
| c.956C>G | A319G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A319G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. In contrast, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM predict pathogenicity, while Rosetta remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -6.505 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.11 | Likely Benign | 0.4 | 0.56 | Ambiguous | 0.34 | Likely Benign | 0.39 | Likely Benign | 0.219 | Likely Benign | -1.83 | Neutral | 0.994 | Probably Damaging | 0.900 | Possibly Damaging | 1.89 | Pathogenic | 0.09 | Tolerated | 0.2345 | 0.4532 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.956C>T | A319V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A319V missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. FoldX, Rosetta, and Foldetta give uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 benign vs 2 pathogenic), and Foldetta is also inconclusive. Overall, the majority of evidence points to a benign effect, and this does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.179055 | Structured | 0.410405 | Uncertain | 0.879 | 0.254 | 0.125 | -8.179 | Likely Pathogenic | 0.141 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.4 | 0.63 | Ambiguous | 0.61 | Ambiguous | 0.23 | Likely Benign | 0.329 | Likely Benign | -2.32 | Neutral | 0.989 | Probably Damaging | 0.824 | Possibly Damaging | 1.88 | Pathogenic | 0.10 | Tolerated | 0.1094 | 0.6390 | 0 | 0 | 2.4 | 28.05 | ||||||||||||||||||||||||||||||
| c.958G>A | V320I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while Rosetta remains inconclusive. High‑accuracy assessments corroborate the benign trend: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the preponderance of evidence points to a benign effect for V320I, and this conclusion does not conflict with the current ClinVar designation of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | Uncertain | 1 | -5.220 | Likely Benign | 0.111 | Likely Benign | Likely Benign | -0.27 | Likely Benign | 0.2 | 0.66 | Ambiguous | 0.20 | Likely Benign | 0.01 | Likely Benign | 0.027 | Likely Benign | -0.21 | Neutral | 0.198 | Benign | 0.114 | Benign | 1.77 | Pathogenic | 0.45 | Tolerated | 3.38 | 23 | 0.0514 | 0.3207 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||||
| c.958G>C | V320L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320L is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437863‑G‑C). Functional prediction tools that agree on benign impact include REVEL, FoldX, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Pathogenic predictions come from polyPhen‑2 HumDiv and FATHMM, while Rosetta, Foldetta, premPS, and AlphaMissense‑Default are inconclusive. The high‑accuracy consensus (SGM Consensus) derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a benign verdict. AlphaMissense‑Optimized also predicts benign, whereas Foldetta remains uncertain. 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. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | Uncertain | 2 | 6-33437863-G-C | 6 | 3.72e-6 | -6.207 | Likely Benign | 0.362 | Ambiguous | Likely Benign | -0.26 | Likely Benign | 0.2 | 1.33 | Ambiguous | 0.54 | Ambiguous | 0.51 | Ambiguous | 0.096 | Likely Benign | -1.02 | Neutral | 0.900 | Possibly Damaging | 0.373 | Benign | 1.78 | Pathogenic | 0.92 | Tolerated | 3.38 | 23 | 0.0661 | 0.3863 | 2 | 1 | -0.4 | 14.03 | 245.8 | -10.2 | 0.3 | 0.9 | 0.1 | 0.3 | X | Potentially Benign | The isopropyl side chain of Val310, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), hydrophobically packs with the side chains of nearby residues (e.g., Leu286, Val350, Pro318). The hydrophobic Leu320 side chain mostly forms the same interactions; hence, the residue swap does not seem to negatively affect the protein structure based on the variant simulations. | ||||||||||||||
| c.958G>T | V320F 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant V320F is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign impact include REVEL, premPS, and SIFT, whereas tools that agree on pathogenic impact include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as inconclusive, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as inconclusive. Because the majority of available predictions and the SGM‑Consensus favor pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for V320F. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -9.958 | Likely Pathogenic | 0.877 | Likely Pathogenic | Ambiguous | 1.49 | Ambiguous | 1.4 | 1.55 | Ambiguous | 1.52 | Ambiguous | 0.44 | Likely Benign | 0.237 | Likely Benign | -3.26 | Deleterious | 0.994 | Probably Damaging | 0.944 | Probably Damaging | 1.79 | Pathogenic | 0.06 | Tolerated | 0.0473 | 0.3064 | -1 | -1 | -1.4 | 48.04 | |||||||||||||||||||||||||||||
| c.959T>A | V320D 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V320D is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from REVEL and SIFT; pathogenic predictions from premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Stability‑based methods FoldX and Rosetta returned uncertain results, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also yielded an uncertain prediction. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a pathogenic effect, which is consistent with the lack of ClinVar annotation and gnomAD absence. Thus, the variant is most likely pathogenic, and this prediction does not contradict ClinVar status because ClinVar has no entry for it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -11.269 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 1.99 | Ambiguous | 1.0 | 1.67 | Ambiguous | 1.83 | Ambiguous | 1.50 | Destabilizing | 0.405 | Likely Benign | -5.58 | Deleterious | 0.999 | Probably Damaging | 0.972 | Probably Damaging | 1.93 | Pathogenic | 0.07 | Tolerated | 0.1101 | 0.0482 | -2 | -3 | -7.7 | 15.96 | |||||||||||||||||||||||||||||
| c.959T>C | V320A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V320A missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and FATHMM. Four tools (AlphaMissense‑Default, FoldX, Rosetta, Foldetta) give uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, more tools (five) predict pathogenicity than benign (four), and the high‑accuracy consensus leans toward pathogenic. Thus, 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. | C2 | 0.185198 | Structured | 0.419626 | Uncertain | 0.905 | 0.266 | 0.125 | -5.488 | Likely Benign | 0.545 | Ambiguous | Likely Benign | 1.26 | Ambiguous | 0.7 | 1.48 | Ambiguous | 1.37 | Ambiguous | 1.27 | Destabilizing | 0.179 | Likely Benign | -3.05 | Deleterious | 0.948 | Possibly Damaging | 0.761 | Possibly Damaging | 1.84 | Pathogenic | 0.35 | Tolerated | 0.2405 | 0.1903 | 0 | 0 | -2.4 | -28.05 | ||||||||||||||||||||||||||||||
| c.961C>A | R321S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R321S is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Two tools—FoldX 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 benign. Overall, the majority of predictions lean toward a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | -10.146 | Likely Pathogenic | 0.497 | Ambiguous | Likely Benign | 0.66 | Ambiguous | 0.1 | -0.30 | Likely Benign | 0.18 | Likely Benign | 0.24 | Likely Benign | 0.379 | Likely Benign | -2.27 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.00 | Pathogenic | 0.10 | Tolerated | 0.2958 | 0.2785 | 0 | -1 | 3.7 | -69.11 | ||||||||||||||||||||||||||||||
| c.962G>A | R321H 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R321H is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6‑33437867‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM, while premPS remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of predictions support a benign impact, and this consensus does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.175930 | Structured | 0.423273 | Uncertain | 0.931 | 0.297 | 0.125 | Uncertain | 1 | 6-33437867-G-A | 8 | 4.96e-6 | -8.751 | Likely Pathogenic | 0.136 | Likely Benign | Likely Benign | 0.48 | Likely Benign | 0.1 | -0.36 | Likely Benign | 0.06 | Likely Benign | 0.59 | Ambiguous | 0.323 | Likely Benign | -1.43 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.92 | Pathogenic | 0.25 | Tolerated | 3.38 | 23 | 0.2930 | 0.0936 | 2 | 0 | 1.3 | -19.05 | 218.5 | 86.9 | 1.1 | 0.0 | 0.3 | 0.0 | X | Potentially Benign | The guanidinium group of Arg321, located in a β hairpin loop linking two anti-parallel β sheet strands (res. Thr305-Asn315, res. Ala322-Asp330), faces outward without forming any stable interactions in the WT simulations. Similarly, in the variant simulations, the imidazole ring of His321 also points outward without making any stable intra-protein interactions. Thus, the residue swap does not seem to cause adverse effects on the protein structure based on the simulations. However, β hairpins are potential nucleation sites during the initial stages of protein folding, so even minor changes in them could be significant. | ||||||||||||||
| c.964G>A | A322T 2D AIThe SynGAP1 missense variant A322T is not reported in ClinVar and is absent from gnomAD. Consensus from most in silico predictors classifies the change as benign: SGM‑Consensus (Likely Benign), REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect. Only FATHMM indicates a pathogenic signal, while FoldX and premPS are inconclusive. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign impact on protein stability. Overall, the majority of evidence supports a benign effect for A322T, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -2.252 | Likely Benign | 0.064 | Likely Benign | Likely Benign | 0.58 | Ambiguous | 0.9 | 0.22 | Likely Benign | 0.40 | Likely Benign | -0.52 | Ambiguous | 0.112 | Likely Benign | 0.20 | Neutral | 0.010 | Benign | 0.005 | Benign | 1.95 | Pathogenic | 0.73 | Tolerated | 0.1367 | 0.6432 | 1 | 0 | -2.5 | 30.03 | |||||||||||||||||||||||||||||
| c.964G>C | A322P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, and SIFT, while pathogenic calls are made by SGM‑Consensus, Rosetta, Foldetta, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: FoldX and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Overall, the majority of evidence points to a pathogenic effect. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Thus, the variant is most likely pathogenic, with no ClinVar evidence to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -10.558 | Likely Pathogenic | 0.878 | Likely Pathogenic | Ambiguous | 1.26 | Ambiguous | 1.3 | 5.43 | Destabilizing | 3.35 | Destabilizing | 0.40 | Likely Benign | 0.343 | Likely Benign | -1.72 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.90 | Pathogenic | 0.18 | Tolerated | 0.2064 | 0.5400 | 1 | -1 | -3.4 | 26.04 | |||||||||||||||||||||||||||||
| c.964G>T | A322S 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322S is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as benign. Only FATHMM predicts a pathogenic outcome. Grouping by consensus, the benign‑predicting tools outnumber the single pathogenic prediction. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports “Likely Benign”; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also indicates a benign effect. No prediction or 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 reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -1.424 | Likely Benign | 0.058 | Likely Benign | Likely Benign | 0.41 | Likely Benign | 0.2 | 0.38 | Likely Benign | 0.40 | Likely Benign | -0.44 | Likely Benign | 0.127 | Likely Benign | 1.09 | Neutral | 0.010 | Benign | 0.010 | Benign | 2.00 | Pathogenic | 0.67 | Tolerated | 0.2696 | 0.5253 | 1 | 1 | -2.6 | 16.00 | |||||||||||||||||||||||||||||
| c.965C>A | A322D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 A322D missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The remaining tools—FoldX, Rosetta, ESM1b, and AlphaMissense‑Default—return uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta indicates no significant stability change (uncertain). Overall, the preponderance of evidence (seven benign predictions versus one pathogenic) 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 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -7.184 | In-Between | 0.411 | Ambiguous | Likely Benign | 0.65 | Ambiguous | 0.1 | 1.35 | Ambiguous | 1.00 | Ambiguous | 0.34 | Likely Benign | 0.246 | Likely Benign | -0.95 | Neutral | 0.270 | Benign | 0.136 | Benign | 1.96 | Pathogenic | 0.32 | Tolerated | 0.1646 | 0.1660 | 0 | -2 | -5.3 | 44.01 | ||||||||||||||||||||||||||||||
| c.965C>G | A322G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant A322G is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score. Only FATHMM predicts a pathogenic outcome. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain or inconclusive and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Based on the preponderance of benign predictions and the lack of contradictory evidence, the variant is most likely benign; this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -5.230 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.84 | Ambiguous | 0.1 | 1.43 | Ambiguous | 1.14 | Ambiguous | 0.64 | Ambiguous | 0.054 | Likely Benign | -1.07 | Neutral | 0.139 | Benign | 0.088 | Benign | 1.94 | Pathogenic | 0.19 | Tolerated | 0.2513 | 0.4683 | 1 | 0 | -2.2 | -14.03 | |||||||||||||||||||||||||||||
| c.965C>T | A322V 2D AIThe SynGAP1 missense variant A322V is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No predictions or stability results are missing or inconclusive. Based on the overwhelming consensus of the available tools, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.175930 | Structured | 0.425745 | Uncertain | 0.938 | 0.334 | 0.000 | -4.905 | Likely Benign | 0.121 | Likely Benign | Likely Benign | 0.02 | Likely Benign | 1.0 | -0.42 | Likely Benign | -0.20 | Likely Benign | 0.19 | Likely Benign | 0.052 | Likely Benign | -1.63 | Neutral | 0.270 | Benign | 0.136 | Benign | 1.96 | Pathogenic | 0.22 | Tolerated | 0.1279 | 0.6126 | 0 | 0 | 2.4 | 28.05 | |||||||||||||||||||||||||||||
| c.967C>G | L323V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L323V is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions (REVEL, premPS, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic predictions (FoldX, Rosetta, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM). The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled Likely Benign. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign; the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates Likely Benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts pathogenic. Overall, the majority of evidence points to a benign effect, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.428564 | Uncertain | 0.956 | 0.369 | 0.000 | -3.483 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 2.18 | Destabilizing | 0.3 | 2.22 | Destabilizing | 2.20 | Destabilizing | 0.17 | Likely Benign | 0.227 | Likely Benign | 0.19 | Neutral | 0.898 | Possibly Damaging | 0.472 | Possibly Damaging | 0.80 | Pathogenic | 0.80 | Tolerated | 0.1277 | 0.2656 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.970C>G | R324G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324G is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect comprise FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default; the SGM‑Consensus score is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. With the majority of evidence pointing to deleterious impact and two of the three high‑accuracy methods supporting pathogenicity, the variant is most likely pathogenic. This conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | -12.266 | Likely Pathogenic | 0.708 | Likely Pathogenic | Likely Benign | 2.99 | Destabilizing | 0.1 | 3.18 | Destabilizing | 3.09 | Destabilizing | 1.27 | Destabilizing | 0.496 | Likely Benign | -2.64 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.84 | Pathogenic | 0.39 | Tolerated | 0.3546 | 0.4135 | -3 | -2 | 4.1 | -99.14 | |||||||||||||||||||||||||||||
| c.970C>T | R324W 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant R324W is listed in ClinVar with an uncertain significance (ClinVar ID 845180.0) and is present in gnomAD (ID 6‑33437875‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability or functional scores are available. Overall, the preponderance of evidence points to a pathogenic effect, which does not contradict the ClinVar uncertain status but suggests a leaning toward pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | Uncertain | 1 | 6-33437875-C-T | 2 | 1.24e-6 | -12.906 | Likely Pathogenic | 0.694 | Likely Pathogenic | Likely Benign | 1.49 | Ambiguous | 0.3 | 0.56 | Ambiguous | 1.03 | Ambiguous | 0.66 | Ambiguous | 0.481 | Likely Benign | -3.12 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.82 | Pathogenic | 0.16 | Tolerated | 3.39 | 22 | 0.1517 | 0.4361 | 2 | -3 | 3.6 | 30.03 | 256.6 | 39.1 | 0.0 | 0.1 | 0.3 | 0.2 | X | Potentially Pathogenic | The guanidinium group of Arg324, located at the end of an anti-parallel β sheet strand (res. Ala322-Asp330), faces outward and frequently forms a salt bridge with the carboxylate group of the Asp288 side chain, which is part of a β strand end (res. Met289-Pro298). In the variant simulations, the indole ring of the Trp324 side chain cannot maintain a similar interaction with the negatively charged carboxylate side chain of Asp288, potentially compromising the folding of the anti-parallel β sheet assembly. However, the residue swap does not appear to negatively impact the protein structure or its integrity based on the simulations. | |||||||||||||
| c.971G>A | R324Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant R324Q is listed in ClinVar with an uncertain significance (ClinVar ID 2572558.0) and is present in gnomAD (ID 6‑33437876‑G‑A). Prediction tools that classify the variant as benign include REVEL, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. 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 indicates a likely benign outcome. Protein‑stability predictions from FoldX, Rosetta, and the combined Foldetta method are all uncertain. Overall, the consensus of available computational evidence points to a benign effect for R324Q, which is consistent with its ClinVar status of uncertain significance rather than a pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | Uncertain | 3 | 6-33437876-G-A | 3 | 1.86e-6 | -5.001 | Likely Benign | 0.173 | Likely Benign | Likely Benign | 0.56 | Ambiguous | 0.1 | 0.63 | Ambiguous | 0.60 | Ambiguous | 1.02 | Destabilizing | 0.307 | Likely Benign | -1.17 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 1.92 | Pathogenic | 0.41 | Tolerated | 3.39 | 22 | 0.3804 | 0.3214 | 1 | 1 | 1.0 | -28.06 | ||||||||||||||||||||||
| c.971G>C | R324P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, PROVEAN, and SIFT, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic” because three of the four contributing tools predict pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenic. Based on the preponderance of pathogenic predictions—including the high‑accuracy tools—the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | -14.533 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 4.61 | Destabilizing | 0.5 | 2.19 | Destabilizing | 3.40 | Destabilizing | 1.03 | Destabilizing | 0.486 | Likely Benign | -2.15 | Neutral | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 1.83 | Pathogenic | 0.29 | Tolerated | 0.2291 | 0.5556 | 0 | -2 | 2.9 | -59.07 | |||||||||||||||||||||||||||||
| c.971G>T | R324L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant R324L is catalogued in gnomAD (6-33437876‑G‑T) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, and SIFT; pathogenic predictions arise from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts a benign effect, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome, and Foldetta (integrating FoldX‑MD and Rosetta outputs) reports a benign stability change. Overall, the majority of evidence points toward a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.257454 | Structured | 0.426893 | Uncertain | 0.954 | 0.397 | 0.000 | 6-33437876-G-T | 1 | 6.20e-7 | -10.328 | Likely Pathogenic | 0.575 | Likely Pathogenic | Likely Benign | -0.28 | Likely Benign | 0.0 | -0.08 | Likely Benign | -0.18 | Likely Benign | 0.29 | Likely Benign | 0.489 | Likely Benign | -2.20 | Neutral | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.86 | Pathogenic | 0.63 | Tolerated | 3.39 | 22 | 0.2310 | 0.5607 | -2 | -3 | 8.3 | -43.03 | ||||||||||||||||||||||||
| c.973C>G | L325V 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L325V is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Rosetta and Foldetta give uncertain results. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.352862 | Structured | 0.424577 | Uncertain | 0.955 | 0.436 | 0.000 | -3.104 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 2.26 | Destabilizing | 0.1 | 1.27 | Ambiguous | 1.77 | Ambiguous | -0.39 | Likely Benign | 0.183 | Likely Benign | 0.16 | Neutral | 0.898 | Possibly Damaging | 0.472 | Possibly Damaging | 1.68 | Pathogenic | 1.00 | Tolerated | 0.1571 | 0.3957 | 2 | 1 | 0.4 | -14.03 | |||||||||||||||||||||||||||||
| c.976C>A | H326N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326N has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and SIFT, whereas a majority (seven) predict a pathogenic outcome: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, AlphaMissense‑Optimized) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the balance of evidence points to a pathogenic impact for H326N, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -8.914 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.81 | Ambiguous | 0.2 | 1.48 | Ambiguous | 1.15 | Ambiguous | 0.97 | Ambiguous | 0.409 | Likely Benign | -5.63 | Deleterious | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 1.95 | Pathogenic | 0.11 | Tolerated | 0.1929 | 0.2552 | 2 | 1 | -0.3 | -23.04 | |||||||||||||||||||||||||||||
| c.976C>G | H326D 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H326D 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 SIFT, which scores the variant as benign. All other evaluated algorithms—REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. Tools with inconclusive results are FoldX, Foldetta, and premPS, which are listed as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a pathogenic verdict. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, reports an uncertain result. Overall, the preponderance of evidence indicates 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 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -13.000 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.87 | Ambiguous | 0.6 | 2.00 | Destabilizing | 1.44 | Ambiguous | 0.96 | Ambiguous | 0.561 | Likely Pathogenic | -7.67 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.04 | Pathogenic | 0.10 | Tolerated | 0.2612 | 0.1611 | 1 | -1 | -0.3 | -22.05 | |||||||||||||||||||||||||||||
| c.977A>G | H326R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H326R missense variant is not listed in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include SIFT and Foldetta, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict a pathogenic impact. High‑accuracy methods give the following results: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM‑Consensus, which is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as likely pathogenic; Foldetta, a protein‑folding stability approach that integrates FoldX‑MD and Rosetta outputs, predicts a benign effect. Because the majority of evidence points to a deleterious change, the variant is most likely pathogenic, and this assessment is not contradicted by the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -12.369 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | -0.65 | Ambiguous | 0.1 | 1.40 | Ambiguous | 0.38 | Likely Benign | 0.83 | Ambiguous | 0.601 | Likely Pathogenic | -6.89 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.97 | Pathogenic | 0.10 | Tolerated | 0.1832 | 0.2413 | 2 | 0 | -1.3 | 19.05 | |||||||||||||||||||||||||||||
| c.977A>T | H326L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 H326L missense variant is not reported in ClinVar (status: None) and has no entry in gnomAD. Prediction tools that agree on a benign effect include SIFT, premPS, Rosetta, and Foldetta. Tools that agree on a pathogenic effect include REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy methods give mixed results: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts likely pathogenic; and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) predicts benign. No evidence is available from FoldX or AlphaMissense‑Optimized to support either outcome. Overall, the majority of predictions (nine pathogenic vs. four benign) indicate that H326L 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 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -10.421 | Likely Pathogenic | 0.888 | Likely Pathogenic | Ambiguous | -0.85 | Ambiguous | 0.2 | 0.36 | Likely Benign | -0.25 | Likely Benign | 0.44 | Likely Benign | 0.627 | Likely Pathogenic | -9.64 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.95 | Pathogenic | 0.08 | Tolerated | 0.0992 | 0.5799 | -2 | -3 | 7.0 | -23.98 | |||||||||||||||||||||||||||||
| c.978T>A | H326Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, whereas a majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Foldetta (combining FoldX‑MD and Rosetta) and Rosetta alone, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for H326Q. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -8.688 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.67 | Ambiguous | 1.07 | Ambiguous | 1.00 | Destabilizing | 0.444 | Likely Benign | -6.89 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.07 | Pathogenic | 0.10 | Tolerated | 0.1485 | 0.3500 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.978T>G | H326Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant H326Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, whereas a majority of tools predict a pathogenic outcome: premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Pathogenic). Two tools, Foldetta (combining FoldX‑MD and Rosetta) and Rosetta alone, return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus also indicates likely pathogenic, while Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for H326Q. This conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.342579 | Structured | 0.418150 | Uncertain | 0.944 | 0.455 | 0.000 | -8.688 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.46 | Likely Benign | 0.1 | 1.67 | Ambiguous | 1.07 | Ambiguous | 1.00 | Destabilizing | 0.444 | Likely Benign | -6.89 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.07 | Pathogenic | 0.10 | Tolerated | 0.1485 | 0.3500 | 3 | 0 | -0.3 | -9.01 | |||||||||||||||||||||||||||||
| c.979C>G | L327V 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L327V is reported in gnomAD (ID 6‑33437884‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.335645 | Structured | 0.409189 | Uncertain | 0.939 | 0.490 | 0.000 | 6-33437884-C-G | 3 | 1.86e-6 | -8.978 | Likely Pathogenic | 0.148 | Likely Benign | Likely Benign | 1.38 | Ambiguous | 0.1 | 0.67 | Ambiguous | 1.03 | Ambiguous | 1.31 | Destabilizing | 0.208 | Likely Benign | -1.87 | Neutral | 0.999 | Probably Damaging | 0.994 | Probably Damaging | 2.66 | Benign | 0.13 | Tolerated | 3.38 | 23 | 0.1648 | 0.4206 | 1 | 2 | 0.4 | -14.03 | ||||||||||||||||||||||||
| c.983A>T | Y328F 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Y328F is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, 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 benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.411940 | Structured | 0.392519 | Uncertain | 0.916 | 0.497 | 0.000 | -6.770 | Likely Benign | 0.444 | Ambiguous | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.43 | Likely Benign | 0.39 | Likely Benign | 0.37 | Likely Benign | 0.330 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.992 | Probably Damaging | 1.67 | Pathogenic | 0.16 | Tolerated | 0.2409 | 0.3643 | 7 | 3 | 4.1 | -16.00 | ||||||||||||||||||||||||||||||
| c.989A>C | D330A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330A missense variant is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL and SIFT, while a majority of tools predict a pathogenic impact: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized—do not provide definitive evidence. High‑accuracy methods give the following: SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely pathogenic outcome; AlphaMissense‑Optimized is uncertain; Foldetta is also uncertain. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for D330A. This conclusion is not contradicted by ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -14.051 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 1.75 | Ambiguous | 0.3 | 1.06 | Ambiguous | 1.41 | Ambiguous | 0.60 | Ambiguous | 0.399 | Likely Benign | -5.49 | Deleterious | 0.961 | Probably Damaging | 0.655 | Possibly Damaging | 0.93 | Pathogenic | 0.11 | Tolerated | 0.4087 | 0.4476 | 0 | -2 | 5.3 | -44.01 | |||||||||||||||||||||||||||||
| c.990C>A | D330E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and FATHMM. The remaining tools—FoldX, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -3.427 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.98 | Ambiguous | 0.2 | 2.31 | Destabilizing | 1.65 | Ambiguous | 0.39 | Likely Benign | 0.073 | Likely Benign | -1.38 | Neutral | 0.122 | Benign | 0.030 | Benign | 0.97 | Pathogenic | 0.67 | Tolerated | 0.1464 | 0.4416 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.990C>G | D330E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D330E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are Rosetta and FATHMM. The remaining tools—FoldX, AlphaMissense‑Default, and Foldetta—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by any ClinVar annotation, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.380708 | Structured | 0.360008 | Uncertain | 0.805 | 0.488 | 0.250 | -3.427 | Likely Benign | 0.407 | Ambiguous | Likely Benign | 0.98 | Ambiguous | 0.2 | 2.31 | Destabilizing | 1.65 | Ambiguous | 0.39 | Likely Benign | 0.075 | Likely Benign | -1.38 | Neutral | 0.122 | Benign | 0.030 | Benign | 0.97 | Pathogenic | 0.67 | Tolerated | 0.1464 | 0.4416 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.991T>A | S331T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while FoldX and premPS are inconclusive (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Taken together, the majority of evidence indicates that S331T is most likely benign, and this conclusion does not contradict the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -2.474 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.2 | -0.10 | Likely Benign | 0.25 | Likely Benign | -0.72 | Ambiguous | 0.095 | Likely Benign | 1.13 | Neutral | 0.003 | Benign | 0.002 | Benign | 1.86 | Pathogenic | 0.98 | Tolerated | 0.1505 | 0.4552 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.991T>C | S331P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, ESM1b, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are Rosetta, polyPhen‑2 HumDiv, and FATHMM. Two tools give inconclusive results: AlphaMissense‑Default and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation and gnomAD presence, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -5.104 | Likely Benign | 0.409 | Ambiguous | Likely Benign | 0.33 | Likely Benign | 0.2 | 2.35 | Destabilizing | 1.34 | Ambiguous | 0.44 | Likely Benign | 0.186 | Likely Benign | -1.81 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.83 | Pathogenic | 0.26 | Tolerated | 0.2306 | 0.4086 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.991T>G | S331A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a benign majority vote (3 benign vs. 1 pathogenic). High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote) is benign; and Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. No prediction or folding‑stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -2.199 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.22 | Likely Benign | 0.1 | -0.08 | Likely Benign | 0.07 | Likely Benign | -0.15 | Likely Benign | 0.071 | Likely Benign | -0.44 | Neutral | 0.139 | Benign | 0.060 | Benign | 1.89 | Pathogenic | 0.67 | Tolerated | 0.5314 | 0.3008 | Weaken | 1 | 1 | 2.6 | -16.00 | ||||||||||||||||||||||||||||
| c.992C>T | S331L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S331L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only FATHMM predicts pathogenicity, while FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the consensus of the majority of tools supports a benign classification, and this is consistent with the lack of ClinVar evidence; there is no contradiction with ClinVar status. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.346458 | Uncertain | 0.658 | 0.475 | 0.250 | -6.570 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.54 | Ambiguous | 0.0 | 1.06 | Ambiguous | 0.80 | Ambiguous | 0.07 | Likely Benign | 0.090 | Likely Benign | -1.72 | Neutral | 0.270 | Benign | 0.136 | Benign | 1.87 | Pathogenic | 0.58 | Tolerated | 0.0953 | 0.4124 | -3 | -2 | 4.6 | 26.08 | |||||||||||||||||||||||||||||
| c.994G>A | D332N 2D 3DClick to see structure in 3D Viewer AISynGAP1 D332N is not reported in ClinVar and is absent from gnomAD. Benign predictions come from REVEL, Rosetta, premPS, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default; SGM‑Consensus indicates a likely pathogenic outcome. FoldX and Foldetta give uncertain results. High‑accuracy tools show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as uncertain. Overall, the majority of conventional predictors lean toward pathogenicity, but the high‑accuracy AlphaMissense‑Optimized result is benign and Foldetta is inconclusive. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -10.931 | Likely Pathogenic | 0.771 | Likely Pathogenic | Likely Benign | 1.20 | Ambiguous | 0.1 | -0.16 | Likely Benign | 0.52 | Ambiguous | 0.49 | Likely Benign | 0.396 | Likely Benign | -4.14 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.32 | Pathogenic | 0.11 | Tolerated | 0.0785 | 0.3963 | 2 | 1 | 0.0 | -0.98 | |||||||||||||||||||||||||||||
| c.995A>G | D332G 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332G missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic impact. Predictions that are inconclusive or uncertain are given by 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, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for D332G, 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 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -10.844 | Likely Pathogenic | 0.860 | Likely Pathogenic | Ambiguous | 1.78 | Ambiguous | 0.3 | 0.69 | Ambiguous | 1.24 | Ambiguous | 0.63 | Ambiguous | 0.539 | Likely Pathogenic | -5.98 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.31 | Pathogenic | 0.07 | Tolerated | 0.3052 | 0.4765 | 1 | -1 | 3.1 | -58.04 | |||||||||||||||||||||||||||||
| c.996C>A | D332E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332E missense change is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive because it yields a 2‑to‑2 split. Overall, the majority of evidence points to a benign effect. 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. | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -4.915 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.04 | Likely Benign | 0.27 | Likely Benign | 0.35 | Likely Benign | 0.191 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.29 | Pathogenic | 0.24 | Tolerated | 0.0970 | 0.3915 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.996C>G | D332E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D332E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign classification. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.339168 | Structured | 0.336528 | Uncertain | 0.537 | 0.445 | 0.375 | -4.915 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.50 | Ambiguous | 0.2 | 0.04 | Likely Benign | 0.27 | Likely Benign | 0.35 | Likely Benign | 0.188 | Likely Benign | -2.66 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.29 | Pathogenic | 0.24 | Tolerated | 0.0970 | 0.3915 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.997A>C | K333Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 K333Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, and SIFT, while those that agree on a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). Tools with inconclusive results are AlphaMissense‑Optimized, Foldetta, premPS, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign (combining FoldX‑MD and Rosetta outputs). Overall, the majority of evidence points toward a pathogenic classification, which does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -11.647 | Likely Pathogenic | 0.866 | Likely Pathogenic | Ambiguous | 0.00 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.26 | Likely Benign | 0.76 | Ambiguous | 0.444 | Likely Benign | -3.11 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.08 | Tolerated | 0.4015 | 0.1219 | 1 | 1 | 0.4 | -0.04 | |||||||||||||||||||||||||||||
| c.997A>G | K333E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 K333E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and SIFT. Tools that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a pathogenic impact for K333E. This conclusion is not contradicted by ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -14.059 | Likely Pathogenic | 0.991 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.30 | Likely Benign | 0.12 | Likely Benign | 0.89 | Ambiguous | 0.488 | Likely Benign | -3.21 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.91 | Pathogenic | 0.09 | Tolerated | 0.3429 | 0.1039 | 0 | 1 | 0.4 | 0.94 | |||||||||||||||||||||||||||||
| c.998A>C | K333T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K333T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include Rosetta, Foldetta, premPS, and SIFT, whereas a larger set—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score—predict a pathogenic impact. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) reports a benign effect. Overall, the majority of evidence points to a pathogenic effect for K333T, and this conclusion does not conflict with 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 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -11.358 | Likely Pathogenic | 0.949 | Likely Pathogenic | Ambiguous | 0.51 | Ambiguous | 0.0 | -0.15 | Likely Benign | 0.18 | Likely Benign | 0.46 | Likely Benign | 0.506 | Likely Pathogenic | -4.82 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.96 | Pathogenic | 0.08 | Tolerated | 0.1839 | 0.3354 | 0 | -1 | 3.2 | -27.07 | |||||||||||||||||||||||||||||
| c.998A>G | K333R 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant K333R is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus “Likely Benign”) and pathogenic (polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM). High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign”, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence points to a benign effect for K333R, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -4.897 | Likely Benign | 0.120 | Likely Benign | Likely Benign | -0.23 | Likely Benign | 0.0 | 0.15 | Likely Benign | -0.04 | Likely Benign | 0.33 | Likely Benign | 0.232 | Likely Benign | -2.02 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 2.01 | Pathogenic | 0.14 | Tolerated | 0.4294 | 0.1134 | 3 | 2 | -0.6 | 28.01 | |||||||||||||||||||||||||||||
| c.999A>C | K333N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K333N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split opinion: benign predictions come from REVEL, FoldX, Rosetta, and SIFT, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy subset yields contrasting results: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus also indicates Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) predicts benign. premPS is inconclusive. Overall, the majority of tools lean toward pathogenicity, and the high‑accuracy predictions are not uniformly supportive of benign status. Therefore, K333N is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -11.821 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.36 | Likely Benign | 0.55 | Ambiguous | 0.359 | Likely Benign | -4.03 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.13 | Tolerated | 0.3267 | 0.1315 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
| c.999A>T | K333N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant K333N has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, and SIFT, whereas a larger group predicts pathogenicity: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). The high‑accuracy methods give mixed results: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) reports a benign stability change. premPS is inconclusive and is treated as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.311707 | Structured | 0.330781 | Uncertain | 0.537 | 0.447 | 0.500 | -11.821 | Likely Pathogenic | 0.989 | Likely Pathogenic | Likely Pathogenic | 0.30 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.36 | Likely Benign | 0.55 | Ambiguous | 0.366 | Likely Benign | -4.03 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.91 | Pathogenic | 0.13 | Tolerated | 0.3267 | 0.1315 | 1 | 0 | 0.4 | -14.07 | |||||||||||||||||||||||||||||
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