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.3108G>C | Q1036H 2D  AIThe SynGAP1 missense variant Q1036H 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 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) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | -4.189 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.18 | Neutral | 0.977 | Probably Damaging | 0.615 | Possibly Damaging | 2.50 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0.1641 | 0.4835 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3108G>T | Q1036H 2D AIThe SynGAP1 missense variant Q1036H is listed in gnomAD (ID 6‑33443660‑G‑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). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data are missing. Overall, the majority of reliable predictors indicate a benign impact, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.948786 | Disordered | 0.987955 | Binding | 0.275 | 0.765 | 0.625 | 6-33443660-G-T | 1 | 6.20e-7 | -4.189 | Likely Benign | 0.536 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.18 | Neutral | 0.977 | Probably Damaging | 0.615 | Possibly Damaging | 2.50 | Benign | 0.29 | Tolerated | 3.77 | 5 | 0.1641 | 0.4835 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||
| c.3126G>C | Q1042H 2D AIThe SynGAP1 missense variant Q1042H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.258 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.302 | Likely Benign | -1.54 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2207 | 0.4671 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3126G>T | Q1042H 2D AIThe SynGAP1 missense variant Q1042H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.969315 | Disordered | 0.959333 | Binding | 0.310 | 0.846 | 0.625 | -4.258 | Likely Benign | 0.335 | Likely Benign | Likely Benign | 0.302 | Likely Benign | -1.54 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 0.2207 | 0.4671 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3192G>C | Q1064H 2D AIThe SynGAP1 missense variant Q1064H is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence—including high‑accuracy tools—points to a benign effect, and this conclusion does not contradict the current ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978316 | Disordered | 0.953106 | Binding | 0.378 | 0.914 | 0.875 | Uncertain | 1 | -4.576 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.66 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 4.15 | Benign | 0.05 | Affected | 0.2467 | 0.4243 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3192G>T | Q1064H 2D AIThe SynGAP1 missense variant Q1064H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1064H, 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 | 0.978316 | Disordered | 0.953106 | Binding | 0.378 | 0.914 | 0.875 | -4.576 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -0.66 | Neutral | 0.938 | Possibly Damaging | 0.596 | Possibly Damaging | 4.15 | Benign | 0.05 | Affected | 0.2467 | 0.4243 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3207G>C | Q1069H 2D AIThe SynGAP1 missense variant Q1069H 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.31 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.69 | Benign | 0.06 | Tolerated | 0.1560 | 0.4678 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3207G>T | Q1069H 2D AIThe SynGAP1 missense variant Q1069H 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 | 0.943310 | Disordered | 0.981477 | Binding | 0.333 | 0.906 | 0.875 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.085 | Likely Benign | -1.31 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.69 | Benign | 0.06 | Tolerated | 0.1560 | 0.4678 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3222G>C | Q1074H 2D AIThe SynGAP1 missense variant Q1074H is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, and the only uncertain call comes from AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that 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 | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -5.051 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.053 | Likely Benign | -0.12 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.67 | Benign | 0.07 | Tolerated | 0.1436 | 0.4407 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3222G>T | Q1074H 2D AIThe SynGAP1 missense variant Q1074H is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Functional prediction tools uniformly favor a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign. No tool predicts pathogenicity, and the only uncertain call comes from AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports the variant as “Likely Benign.” High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that 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 | 0.930790 | Disordered | 0.987006 | Binding | 0.339 | 0.897 | 0.750 | -5.051 | Likely Benign | 0.381 | Ambiguous | Likely Benign | 0.053 | Likely Benign | -0.12 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.67 | Benign | 0.07 | Tolerated | 0.1436 | 0.4407 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3225G>C | Q1075H 2D AIThe SynGAP1 missense variant Q1075H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM‑Consensus also indicates likely benign, while Foldetta data is missing. Overall, the majority of reliable predictors classify the variant as 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 | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -4.616 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.06 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.13 | Tolerated | 0.1457 | 0.4214 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3225G>T | Q1075H 2D AIThe SynGAP1 missense variant Q1075H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM‑Consensus also indicates likely benign, while Foldetta data is missing. Overall, the majority of reliable predictors classify the variant as 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 | 0.922952 | Disordered | 0.988305 | Binding | 0.354 | 0.894 | 0.750 | -4.616 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.072 | Likely Benign | -1.06 | Neutral | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.68 | Benign | 0.13 | Tolerated | 0.1457 | 0.4214 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3246G>C | Q1082H 2D AIThe SynGAP1 missense variant Q1082H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | -4.307 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -1.27 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.4779 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3246G>T | Q1082H 2D AIThe SynGAP1 missense variant Q1082H is listed in gnomAD (ID 6‑33443798‑G‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes, while only SIFT predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. 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 | 0.819762 | Disordered | 0.979325 | Binding | 0.347 | 0.896 | 0.875 | 6-33443798-G-T | -4.307 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -1.27 | Neutral | 0.002 | Benign | 0.002 | Benign | 4.11 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1580 | 0.4779 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3279G>C | Q1093H 2D AIThe SynGAP1 missense variant Q1093H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 0.1600 | 0.5269 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3279G>T | Q1093H 2D AIThe SynGAP1 missense variant Q1093H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983312 | Binding | 0.351 | 0.886 | 1.000 | -4.003 | Likely Benign | 0.337 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.14 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.69 | Benign | 0.02 | Affected | 0.1600 | 0.5269 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3318A>C | Q1106H 2D AIThe SynGAP1 missense variant Q1106H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.893 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1453 | 0.4214 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3318A>T | Q1106H 2D AIThe SynGAP1 missense variant Q1106H is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM; AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar status exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.885302 | Disordered | 0.952043 | Binding | 0.382 | 0.870 | 0.875 | -4.893 | Likely Benign | 0.370 | Ambiguous | Likely Benign | 0.174 | Likely Benign | -3.03 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 1.75 | Pathogenic | 0.03 | Affected | 0.1453 | 0.4214 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||||
| c.3321G>C | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3321G>T | Q1107H 2D AIThe SynGAP1 missense variant Q1107H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.876521 | Disordered | 0.951017 | Binding | 0.393 | 0.880 | 0.875 | -3.546 | Likely Benign | 0.260 | Likely Benign | Likely Benign | 0.136 | Likely Benign | -2.58 | Deleterious | 0.990 | Probably Damaging | 0.796 | Possibly Damaging | 2.51 | Benign | 0.01 | Affected | 0.1514 | 0.4683 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3408G>C | Q1136H 2D AIThe SynGAP1 missense variant Q1136H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence points to a benign effect for Q1136H, 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 | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | -5.658 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.347 | Likely Benign | -1.98 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1482 | 0.4637 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||
| c.3408G>T | Q1136H 2D AIThe SynGAP1 missense variant Q1136H is reported in gnomAD (variant ID 6-33443960‑G‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, 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 itself is 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 is not contradicted by any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.775584 | Binding | 0.321 | 0.884 | 0.875 | 6-33443960-G-T | -5.658 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.347 | Likely Benign | -1.98 | Neutral | 0.989 | Probably Damaging | 0.879 | Possibly Damaging | 5.42 | Benign | 0.03 | Affected | 4.32 | 2 | 0.1482 | 0.4637 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3417G>C | Q1139H 2D AIThe SynGAP1 missense variant Q1139H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -3.962 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.265 | Likely Benign | -2.40 | Neutral | 0.002 | Benign | 0.007 | Benign | 5.41 | Benign | 0.00 | Affected | 0.1313 | 0.3801 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3417G>T | Q1139H 2D AIThe SynGAP1 missense variant Q1139H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the preponderance of benign predictions and the lack of contradictory evidence, the variant is most likely benign. This assessment 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 | 0.908098 | Disordered | 0.721191 | Binding | 0.313 | 0.866 | 1.000 | -3.962 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.265 | Likely Benign | -2.40 | Neutral | 0.002 | Benign | 0.007 | Benign | 5.41 | Benign | 0.00 | Affected | 0.1313 | 0.3801 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.345G>C | Q115H 2D AIThe SynGAP1 missense variant Q115H 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‑Default, and AlphaMissense‑Optimized. Only the two polyPhen‑2 implementations (HumDiv and HumVar) 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, and the SGM‑Consensus is likely benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for Q115H, 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 | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.888 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.99 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.08 | Benign | 0.17 | Tolerated | 0.1248 | 0.3383 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.345G>T | Q115H 2D AIThe SynGAP1 missense variant Q115H 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 a likely benign outcome. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic effect. High‑accuracy assessments further support benignity: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence from multiple prediction algorithms and consensus methods points to a benign classification for Q115H, 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 | 0.784345 | Disordered | 0.657256 | Binding | 0.327 | 0.878 | 0.750 | -3.888 | Likely Benign | 0.277 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.99 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.08 | Benign | 0.17 | Tolerated | 0.1248 | 0.3383 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3678G>C | Q1226H 2D AIThe SynGAP1 missense variant Q1226H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective evidence, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as no ClinVar entry exists for Q1226H. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.529623 | Disordered | 0.432206 | Uncertain | 0.850 | 0.547 | 0.250 | -8.363 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | -3.62 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.75 | Pathogenic | 0.00 | Affected | 0.0913 | 0.3230 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3678G>T | Q1226H 2D AIThe SynGAP1 missense variant Q1226H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—all predict a pathogenic impact. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Based on the collective evidence, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as no ClinVar entry exists for Q1226H. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.529623 | Disordered | 0.432206 | Uncertain | 0.850 | 0.547 | 0.250 | -8.363 | Likely Pathogenic | 0.954 | Likely Pathogenic | Ambiguous | 0.241 | Likely Benign | -3.62 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.75 | Pathogenic | 0.00 | Affected | 0.0913 | 0.3230 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3687A>C | Q1229H 2D AIThe SynGAP1 missense variant Q1229H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evaluated predictors (five out of nine) indicate a pathogenic impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | -6.215 | Likely Benign | 0.505 | Ambiguous | Likely Benign | 0.219 | Likely Benign | -3.36 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.75 | Pathogenic | 0.05 | Affected | 0.0948 | 0.2494 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3687A>T | Q1229H 2D AIThe SynGAP1 missense variant Q1229H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta results are unavailable. Overall, the majority of evaluated predictors (five out of nine) indicate a pathogenic impact, so the variant is most likely pathogenic. 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. | Coiled-coil | 0.490133 | Structured | 0.466729 | Uncertain | 0.865 | 0.544 | 0.375 | -6.215 | Likely Benign | 0.505 | Ambiguous | Likely Benign | 0.219 | Likely Benign | -3.36 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.75 | Pathogenic | 0.05 | Affected | 0.0948 | 0.2494 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3708G>C | Q1236H 2D AIThe SynGAP1 missense variant Q1236H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. AlphaMissense‑Default is uncertain, and no Foldetta (FoldX‑MD + Rosetta) stability result is available, so it does not contribute evidence. Overall, the majority of high‑accuracy and consensus predictions indicate a benign impact, and this is consistent with the lack of ClinVar annotation. 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 | Coiled-coil | 0.680603 | Disordered | 0.567914 | Binding | 0.883 | 0.537 | 0.125 | -6.670 | Likely Benign | 0.530 | Ambiguous | Likely Benign | 0.163 | Likely Benign | -2.43 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.0915 | 0.2213 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3708G>T | Q1236H 2D AIThe SynGAP1 missense variant Q1236H is not reported in ClinVar and is absent from gnomAD. Functional prediction consensus shows a split: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus, whereas pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign. Foldetta stability analysis is not available. 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 | 0.680603 | Disordered | 0.567914 | Binding | 0.883 | 0.537 | 0.125 | -6.670 | Likely Benign | 0.530 | Ambiguous | Likely Benign | 0.163 | Likely Benign | -2.43 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.65 | Benign | 0.01 | Affected | 0.0915 | 0.2213 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3714G>C | Q1238H 2D AIThe SynGAP1 missense variant Q1238H is reported in gnomAD (variant ID 6‑33446706‑G‑C) but has no ClinVar entry. Functional prediction tools split into two groups: benign predictions come from REVEL and AlphaMissense‑Optimized, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely pathogenic, and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar classification (none exists). Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.562014 | Disordered | 0.548882 | Binding | 0.855 | 0.545 | 0.250 | 6-33446706-G-C | 1 | 6.20e-7 | -8.647 | Likely Pathogenic | 0.757 | Likely Pathogenic | Likely Benign | 0.202 | Likely Benign | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.31 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1007 | 0.3004 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||
| c.3714G>T | Q1238H 2D AIThe SynGAP1 missense variant Q1238H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and AlphaMissense‑Optimized, whereas the remaining predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default) all indicate a pathogenic impact. High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized classifies the variant as benign, while the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) labels it as Likely Pathogenic. No Foldetta stability prediction is available. Overall, the preponderance of evidence from multiple independent tools points to a pathogenic effect for Q1238H. This conclusion is not contradicted by ClinVar status, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.562014 | Disordered | 0.548882 | Binding | 0.855 | 0.545 | 0.250 | -8.647 | Likely Pathogenic | 0.757 | Likely Pathogenic | Likely Benign | 0.202 | Likely Benign | -3.49 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.31 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1007 | 0.3004 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3729G>C | Q1243H 2D AIThe SynGAP1 missense variant Q1243H is listed in ClinVar with no submitted interpretation and is present in gnomAD (variant ID 6-33446721‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic classification. 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 | 6-33446721-G-C | 1 | 6.19e-7 | -5.281 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -1.90 | Neutral | 0.991 | Probably Damaging | 0.897 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0943 | 0.1813 | 0 | 3 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||
| c.3729G>T | Q1243H 2D AIThe SynGAP1 missense variant Q1243H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates Likely Benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.545602 | Disordered | 0.433693 | Uncertain | 0.887 | 0.551 | 0.500 | -5.281 | Likely Benign | 0.204 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -1.90 | Neutral | 0.991 | Probably Damaging | 0.897 | Possibly Damaging | 2.65 | Benign | 0.02 | Affected | 3.77 | 5 | 0.0943 | 0.1813 | 0 | 3 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||
| c.3750G>C | Q1250H 2D AIThe SynGAP1 missense variant Q1250H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the overall assessment. Overall, the majority of evidence points to a benign effect for Q1250H, 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 | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.832 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1084 | 0.2139 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3750G>T | Q1250H 2D AIThe SynGAP1 missense variant Q1250H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates 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 Q1250H, 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 | 0.759478 | Disordered | 0.360484 | Uncertain | 0.881 | 0.554 | 0.750 | -4.832 | Likely Benign | 0.252 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.91 | Neutral | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.64 | Benign | 0.02 | Affected | 0.1084 | 0.2139 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3753G>C | Q1251H 2D AIThe SynGAP1 missense variant Q1251H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict deleterious effects, while REVEL predicts a benign outcome. Two tools return uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support a harmful interpretation: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, and AlphaMissense‑Optimized remains inconclusive. No Foldetta stability data are available. Overall, the balance of evidence points to a pathogenic effect for Q1251H, 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 | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | -7.561 | In-Between | 0.937 | Likely Pathogenic | Ambiguous | 0.176 | Likely Benign | -3.71 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.1132 | 0.2399 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3753G>T | Q1251H 2D AIThe SynGAP1 missense variant Q1251H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a predominance of pathogenic calls: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all predict deleterious effects, while REVEL predicts a benign outcome. Two tools return uncertain results: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments further support a harmful interpretation: the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic, and AlphaMissense‑Optimized remains inconclusive. No Foldetta stability data are available. Overall, the balance of evidence points to a pathogenic effect for Q1251H, 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 | 0.771762 | Disordered | 0.363872 | Uncertain | 0.869 | 0.551 | 0.875 | -7.561 | In-Between | 0.937 | Likely Pathogenic | Ambiguous | 0.176 | Likely Benign | -3.71 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 2.44 | Pathogenic | 0.00 | Affected | 0.1132 | 0.2399 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3756G>C | Q1252H 2D AIThe SynGAP1 missense variant Q1252H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as deleterious. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.759478 | Disordered | 0.371411 | Uncertain | 0.850 | 0.544 | 0.875 | -6.891 | Likely Benign | 0.951 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -4.02 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.95 | Pathogenic | 0.00 | Affected | 0.1038 | 0.2149 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3756G>T | Q1252H 2D AIThe SynGAP1 missense variant Q1252H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all classify the variant as damaging. 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 (combining FoldX‑MD and Rosetta outputs) is unavailable for this variant. Overall, the preponderance of evidence from multiple in‑silico predictors indicates that the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.759478 | Disordered | 0.371411 | Uncertain | 0.850 | 0.544 | 0.875 | -6.891 | Likely Benign | 0.951 | Likely Pathogenic | Ambiguous | 0.175 | Likely Benign | -4.02 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.95 | Pathogenic | 0.00 | Affected | 0.1038 | 0.2149 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3774G>C | Q1258H 2D AIThe SynGAP1 missense variant Q1258H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also leans pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Based on the preponderance of pathogenic predictions and the lack of benign consensus, the variant is most likely pathogenic; this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.486429 | Structured | 0.525814 | Binding | 0.859 | 0.577 | 0.250 | -5.465 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.172 | Likely Benign | -3.99 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.95 | Pathogenic | 0.00 | Affected | 0.0735 | 0.3066 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3774G>T | Q1258H 2D AIThe SynGAP1 missense variant Q1258H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority vote) is likely pathogenic; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.486429 | Structured | 0.525814 | Binding | 0.859 | 0.577 | 0.250 | -5.465 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.172 | Likely Benign | -3.99 | Deleterious | 0.998 | Probably Damaging | 0.996 | Probably Damaging | 1.95 | Pathogenic | 0.00 | Affected | 0.0735 | 0.3066 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3885G>C | Q1295H 2D AIThe SynGAP1 missense variant Q1295H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show discordant results: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus score (Likely Pathogenic). High‑accuracy assessments further highlight this split: AlphaMissense‑Optimized predicts a benign effect, whereas the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome. No Foldetta stability analysis is available for this residue. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict any existing ClinVar annotation, as none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | -4.851 | Likely Benign | 0.588 | Likely Pathogenic | Likely Benign | 0.349 | Likely Benign | -4.08 | Deleterious | 0.991 | Probably Damaging | 0.986 | Probably Damaging | 2.24 | Pathogenic | 0.00 | Affected | 0.1345 | 0.3203 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3885G>T | Q1295H 2D AIThe SynGAP1 missense variant Q1295H is catalogued in gnomAD (ID 6‑33447933‑G‑T) but has no ClinVar submission. Functional prediction tools show a split: benign calls come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. When predictions are grouped, 3 tools predict benign and 6 predict pathogenic. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this substitution. Overall, the preponderance of evidence points to a pathogenic effect, and this assessment does not conflict with ClinVar, which currently contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.852992 | Disordered | 0.892719 | Binding | 0.499 | 0.801 | 0.625 | 6-33447933-G-T | -4.851 | Likely Benign | 0.588 | Likely Pathogenic | Likely Benign | 0.349 | Likely Benign | -4.08 | Deleterious | 0.991 | Probably Damaging | 0.986 | Probably Damaging | 2.24 | Pathogenic | 0.00 | Affected | 0.1345 | 0.3203 | 3 | 0 | 0.3 | 9.01 | ||||||||||||||||||||||||||||||||||||||
| c.3894G>C | Q1298H 2D AIThe SynGAP1 missense variant Q1298H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. In contrast, polyPhen‑2 HumDiv and SIFT predict a damaging or pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for Q1298H, 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 | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -4.109 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.074 | Likely Benign | -1.45 | Neutral | 0.938 | Possibly Damaging | 0.377 | Benign | 2.77 | Benign | 0.03 | Affected | 0.1083 | 0.2605 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3894G>T | Q1298H 2D AIThe SynGAP1 missense variant Q1298H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools (polyPhen‑2 HumDiv and SIFT) predict pathogenicity, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign classification, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.895297 | Binding | 0.410 | 0.821 | 0.750 | -4.109 | Likely Benign | 0.203 | Likely Benign | Likely Benign | 0.465 | Likely Benign | -1.45 | Neutral | 0.938 | Possibly Damaging | 0.377 | Benign | 2.77 | Benign | 0.03 | Affected | 0.1083 | 0.2605 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.390A>C | Q130H 2D AIThe SynGAP1 missense variant Q130H is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign effect. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts benign, SGM‑Consensus also predicts 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 evidence, 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 | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.828 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -1.09 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.10 | Benign | 0.01 | Affected | 0.1727 | 0.3970 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.390A>T | Q130H 2D AIThe SynGAP1 missense variant Q130H is not reported in ClinVar and has no entry in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all predict a benign effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT each predict a pathogenic impact. The AlphaMissense‑Default tool remains uncertain, and no Foldetta stability assessment is available. High‑accuracy tools specifically highlight benign predictions: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta data are missing. Overall, the balance of evidence points to a benign effect for the variant, 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 | 0.509769 | Disordered | 0.718853 | Binding | 0.306 | 0.885 | 0.375 | -3.828 | Likely Benign | 0.387 | Ambiguous | Likely Benign | 0.074 | Likely Benign | -1.09 | Neutral | 0.990 | Probably Damaging | 0.969 | Probably Damaging | 4.10 | Benign | 0.01 | Affected | 0.1727 | 0.3970 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3990G>C | Q1330H 2D AIThe SynGAP1 missense variant Q1330H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus also reports it as likely benign, and Foldetta (which integrates FoldX‑MD and Rosetta stability calculations) has no available result for this residue. Based on the preponderance of benign predictions from multiple independent algorithms and the lack of pathogenic evidence, the variant is most likely benign. 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 | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.557 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.91 | Neutral | 0.969 | Probably Damaging | 0.732 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.1190 | 0.3996 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.3990G>T | Q1330H 2D AIThe SynGAP1 missense variant Q1330H is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar) and SIFT. AlphaMissense‑Default remains uncertain, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign effect. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM‑Consensus also reports it as likely benign, and Foldetta (which integrates FoldX‑MD and Rosetta stability calculations) has no available result for this residue. Based on the preponderance of benign predictions from multiple independent algorithms and the lack of pathogenic evidence, the variant is most likely benign. 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 | 0.943310 | Disordered | 0.931969 | Binding | 0.369 | 0.752 | 0.875 | -3.557 | Likely Benign | 0.477 | Ambiguous | Likely Benign | 0.066 | Likely Benign | -1.91 | Neutral | 0.969 | Probably Damaging | 0.732 | Possibly Damaging | 3.91 | Benign | 0.02 | Affected | 0.1190 | 0.3996 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.441A>C | Q147H 2D AIThe SynGAP1 missense variant Q147H is not reported in ClinVar and has no entries in gnomAD, indicating it is not catalogued in these databases. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Overall, the balance of evidence, especially the SGM Consensus and the majority of individual predictors, indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -9.759 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.102 | Likely Benign | -2.70 | Deleterious | 0.380 | Benign | 0.265 | Benign | 3.87 | Benign | 0.01 | Affected | 0.1528 | 0.3220 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.441A>T | Q147H 2D AIThe SynGAP1 missense variant Q147H is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar) and FATHMM, while pathogenic calls arise from PROVEAN, SIFT, ESM1b and AlphaMissense‑Default. Grouping by consensus, four tools predict benign and four predict pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM and PROVEAN—labels the variant as Likely Pathogenic. Foldetta, a protein‑folding stability predictor, has no available result for this residue. Taken together, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.503877 | Binding | 0.349 | 0.840 | 0.625 | -9.759 | Likely Pathogenic | 0.955 | Likely Pathogenic | Ambiguous | 0.102 | Likely Benign | -2.70 | Deleterious | 0.380 | Benign | 0.265 | Benign | 3.87 | Benign | 0.01 | Affected | 0.1528 | 0.3220 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| 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.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.648G>C | Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas those that predict a pathogenic impact are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The high‑accuracy assessment shows AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence favors a pathogenic classification; 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 | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.532 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.0 | 0.30 | Likely Benign | 0.30 | Likely Benign | 0.50 | Likely Benign | 0.638 | Likely Pathogenic | -3.84 | Deleterious | 0.989 | Probably Damaging | 0.809 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 0.1909 | 0.4660 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.648G>T | Q216H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q216H is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, and FATHMM, whereas a larger group predicts pathogenicity: SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.206376 | Structured | 0.396100 | Uncertain | 0.804 | 0.274 | 0.000 | -10.532 | Likely Pathogenic | 0.951 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.0 | 0.30 | Likely Benign | 0.30 | Likely Benign | 0.50 | Likely Benign | 0.638 | Likely Pathogenic | -3.84 | Deleterious | 0.989 | Probably Damaging | 0.809 | Possibly Damaging | 5.85 | Benign | 0.01 | Affected | 0.1909 | 0.4660 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.741G>C | Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include SGM‑Consensus, FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Tools that predict a pathogenic outcome are REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No predictions are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -6.239 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.58 | Ambiguous | 0.579 | Likely Pathogenic | -2.10 | Neutral | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.71 | Benign | 0.02 | Affected | 0.0932 | 0.2558 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.741G>T | Q247H 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant Q247H is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, ESM1b, FATHMM, AlphaMissense‑Optimized, and PROVEAN. Those that predict a pathogenic impact are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default, while premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as benign. No prediction or folding stability result is missing or inconclusive. Based on the overall balance of evidence—seven benign versus five pathogenic predictions, and all high‑accuracy tools indicating benign—the variant is most likely benign. This conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.490133 | Structured | 0.283012 | Uncertain | 0.822 | 0.339 | 0.250 | -6.239 | Likely Benign | 0.583 | Likely Pathogenic | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.02 | Likely Benign | 0.20 | Likely Benign | 0.58 | Ambiguous | 0.579 | Likely Pathogenic | -2.10 | Neutral | 0.995 | Probably Damaging | 0.854 | Possibly Damaging | 5.71 | Benign | 0.02 | Affected | 0.0932 | 0.2558 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||
| c.99A>C | Q33H 2D AIThe SynGAP1 missense variant Q33H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | -0.450 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.95 | Neutral | 0.704 | Possibly Damaging | 0.198 | Benign | 4.16 | Benign | 0.00 | Affected | 0.1856 | 0.4509 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.99A>T | Q33H 2D AIThe SynGAP1 missense variant Q33H is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.436712 | Uncertain | 0.342 | 0.860 | 0.375 | -0.450 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.054 | Likely Benign | -0.95 | Neutral | 0.704 | Possibly Damaging | 0.198 | Benign | 4.16 | Benign | 0.00 | Affected | 0.1856 | 0.4509 | 3 | 0 | 0.3 | 9.01 | |||||||||||||||||||||||||||||||||||||||
| c.109T>C | S37P 2D  AIThe SynGAP1 missense variant S37P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available. Overall, the majority of evidence points to a benign effect for S37P, 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 | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -3.788 | Likely Benign | 0.149 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -1.29 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 3.90 | Benign | 0.00 | Affected | 0.2657 | 0.5327 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.10T>C | S4P 2D AIThe SynGAP1 missense variant S4P 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, 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, two tools—polyPhen‑2 HumDiv and SIFT—predict a pathogenic impact. High‑accuracy methods give a consistent benign signal: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect, 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 | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | -4.131 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.153 | Likely Benign | -0.33 | Neutral | 0.676 | Possibly Damaging | 0.307 | Benign | 4.12 | Benign | 0.00 | Affected | 0.2043 | 0.6112 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.1120T>C | S374P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S374P is reported in gnomAD (6‑33438025‑T‑C) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and Rosetta; FoldX and Foldetta are inconclusive. The high‑accuracy consensus (SGM‑Consensus) is “Likely Benign,” derived from the unanimous benign calls of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. AlphaMissense‑Optimized also predicts benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. There is no ClinVar status to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | 6-33438025-T-C | 1 | 7.85e-7 | -4.849 | Likely Benign | 0.125 | Likely Benign | Likely Benign | 0.66 | Ambiguous | 0.6 | 2.22 | Destabilizing | 1.44 | Ambiguous | 0.34 | Likely Benign | 0.388 | Likely Benign | -0.89 | Neutral | 0.396 | Benign | 0.099 | Benign | 5.30 | Benign | 0.02 | Affected | 4.32 | 13 | 0.3012 | 0.6813 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||
| c.1135T>C | S379P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, Rosetta, and Foldetta; FoldX is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Overall, the majority of evidence—including the high‑accuracy benign predictions—suggests that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | -5.007 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 1.10 | Ambiguous | 0.8 | 2.92 | Destabilizing | 2.01 | Destabilizing | 0.17 | Likely Benign | 0.430 | Likely Benign | -0.41 | Neutral | 0.808 | Possibly Damaging | 0.212 | Benign | 3.83 | Benign | 0.10 | Tolerated | 0.3035 | 0.6594 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1153T>C | S385P 2D 3DClick to see structure in 3D Viewer AISynGAP1 variant S385P is listed in ClinVar with an uncertain significance and is present in gnomAD (variant ID 6-33438058‑T‑C). Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict pathogenicity are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. Predictions from FoldX and Rosetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of computational evidence supports a benign effect, which is consistent with the ClinVar uncertain status and does not contradict it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | Uncertain | 1 | 6-33438058-T-C | -5.431 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.91 | Ambiguous | 0.6 | -0.90 | Ambiguous | 0.01 | Likely Benign | 0.19 | Likely Benign | 0.385 | Likely Benign | -0.26 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 4.63 | Benign | 0.04 | Affected | 4.32 | 3 | 0.2925 | 0.6805 | 1 | -1 | -0.8 | 10.04 | 210.3 | 18.5 | 1.8 | 0.9 | 0.3 | 0.0 | Uncertain | Ser385 is located in the Gly-rich Ω loop (res. Pro364-Pro398) between two anti-parallel β sheet strands (res. Thr359-Pro364, res. Ala399-Ile411). Because the Ω loop is assumed to directly interact with the membrane, it moves arbitrarily throughout the WT solvent simulations. The Ω loop potentially plays a crucial role in the SynGAP-membrane complex association, stability, and dynamics. However, this aspect cannot be fully addressed through solvent simulations alone.Ω loops are known to play major roles in protein functions that require flexibility, and so they are rich in glycine residues, prolines, and, to a lesser extent, small hydrophilic residues to ensure maximum flexibility. Thus, the variant’s Pro385 is potentially tolerated in the Ω loop. However, since the effects on Gly-rich Ω loop dynamics can only be well studied through the SynGAP-membrane complex, no definite conclusions can be drawn. | ||||||||||||||||
| c.1165T>C | S389P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389P is listed in gnomAD (variant ID 6‑33438070‑T‑C) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.703578 | Disordered | 0.417444 | Uncertain | 0.306 | 0.803 | 0.875 | 6-33438070-T-C | -5.286 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 1.85 | Ambiguous | 2.0 | -0.99 | Ambiguous | 0.43 | Likely Benign | 0.16 | Likely Benign | 0.460 | Likely Benign | -0.44 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 5.05 | Benign | 0.01 | Affected | 4.32 | 8 | 0.3098 | 0.7002 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||
| c.1396T>C | S466P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466P is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the only inconclusive result is from premPS (Uncertain). High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts Pathogenic. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -13.107 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.67 | Destabilizing | 0.2 | 2.83 | Destabilizing | 2.75 | Destabilizing | 0.95 | Ambiguous | 0.811 | Likely Pathogenic | -3.02 | Deleterious | 0.995 | Probably Damaging | 0.986 | Probably Damaging | -1.55 | Pathogenic | 0.04 | Affected | 0.1617 | 0.4915 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1411T>C | S471P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471P is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include only polyPhen‑2 HumVar, whereas the remaining evaluated algorithms (REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among the majority of tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -12.379 | Likely Pathogenic | 0.980 | Likely Pathogenic | Likely Pathogenic | 3.65 | Destabilizing | 0.2 | 9.24 | Destabilizing | 6.45 | Destabilizing | 0.84 | Ambiguous | 0.530 | Likely Pathogenic | -4.03 | Deleterious | 0.552 | Possibly Damaging | 0.141 | Benign | -1.31 | Pathogenic | 0.05 | Affected | 0.2007 | 0.4769 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.154T>C | S52P 2D AIThe SynGAP1 missense variant S52P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM, whereas polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default all predict a pathogenic outcome. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two pathogenic versus two benign votes); and Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S52P. This conclusion does not contradict ClinVar, as the variant has no existing ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -10.007 | Likely Pathogenic | 0.797 | Likely Pathogenic | Ambiguous | 0.144 | Likely Benign | -1.28 | Neutral | 0.676 | Possibly Damaging | 0.693 | Possibly Damaging | 4.07 | Benign | 0.00 | Affected | 0.2276 | 0.5909 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.1558T>C | S520P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report a pathogenic outcome, while premPS remains inconclusive. No tool predicts a benign effect. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, is pathogenic. Overall, the evidence strongly supports a pathogenic impact for S520P, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | Uncertain | 1 | -12.707 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.72 | Destabilizing | 0.8 | 8.86 | Destabilizing | 6.29 | Destabilizing | 0.83 | Ambiguous | 0.855 | Likely Pathogenic | -4.57 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.32 | Pathogenic | 0.01 | Affected | 0.2154 | 0.4776 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.1600T>C | S534P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33438843‑T‑C). Functional prediction tools that report a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The high‑accuracy assessments are consistent with a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the aggregate predictions, the variant is most likely benign, which does not contradict the ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | Uncertain | 1 | 6-33438843-T-C | 3 | 1.86e-6 | -5.056 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.40 | Likely Benign | 0.2 | 0.35 | Likely Benign | -0.03 | Likely Benign | 0.47 | Likely Benign | 0.203 | Likely Benign | -3.81 | Deleterious | 0.993 | Probably Damaging | 0.993 | Probably Damaging | 3.32 | Benign | 0.05 | Affected | 3.37 | 35 | 0.2071 | 0.4650 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||
| c.1669T>C | S557P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all indicate a pathogenic or likely pathogenic outcome. No tool in the dataset predicts a benign effect. High‑accuracy assessments reinforce this consensus: AlphaMissense‑Optimized classifies the variant as pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also labels it pathogenic. Based on the uniform predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -15.383 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 6.91 | Destabilizing | 0.4 | 8.79 | Destabilizing | 7.85 | Destabilizing | 1.09 | Destabilizing | 0.934 | Likely Pathogenic | -4.60 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | -1.76 | Pathogenic | 0.01 | Affected | 0.2222 | 0.6239 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1711T>C | S571P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S571P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools uniformly indicate a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as pathogenic, while premPS remains inconclusive. High‑accuracy assessments corroborate this trend: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. Consequently, the aggregate evidence strongly supports a pathogenic effect for S571P, and this conclusion does not conflict with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.045569 | Uncertain | 0.928 | 0.270 | 0.000 | Uncertain | 1 | -14.701 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.18 | Destabilizing | 0.2 | 4.89 | Destabilizing | 4.04 | Destabilizing | 0.87 | Ambiguous | 0.814 | Likely Pathogenic | -4.68 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.30 | Pathogenic | 0.02 | Affected | 0.2195 | 0.3760 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||
| c.1774T>C | S592P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S592P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include only SIFT, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No predictions are inconclusive or missing. Based on the overwhelming agreement among pathogenic predictors and the absence of benign evidence, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.100070 | Uncertain | 0.913 | 0.182 | 0.000 | -14.621 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 4.26 | Destabilizing | 0.1 | 2.36 | Destabilizing | 3.31 | Destabilizing | 1.24 | Destabilizing | 0.909 | Likely Pathogenic | -4.77 | Deleterious | 0.999 | Probably Damaging | 0.993 | Probably Damaging | -1.29 | Pathogenic | 0.11 | Tolerated | 0.2412 | 0.4259 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1810T>C | S604P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include premPS and FATHMM, whereas the remaining tools—REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict it to be pathogenic. High‑accuracy methods give consistent results: AlphaMissense‑Optimized indicates pathogenicity; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also labels the variant as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. Taken together, the overwhelming majority of computational evidence supports a pathogenic classification for S604P, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -10.953 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 3.76 | Destabilizing | 0.3 | 8.40 | Destabilizing | 6.08 | Destabilizing | 0.04 | Likely Benign | 0.512 | Likely Pathogenic | -4.98 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 3.10 | Benign | 0.01 | Affected | 0.2524 | 0.4829 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1858T>C | S620P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S620P is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity uniformly favor a deleterious effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict pathogenicity, while premPS remains uncertain. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is pathogenic. Consequently, the variant is most likely pathogenic, and this prediction is consistent with the absence of a ClinVar entry (no contradiction). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.100377 | Uncertain | 0.936 | 0.219 | 0.000 | -12.208 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | 4.89 | Destabilizing | 0.5 | 12.23 | Destabilizing | 8.56 | Destabilizing | 0.73 | Ambiguous | 0.834 | Likely Pathogenic | -3.62 | Deleterious | 0.998 | Probably Damaging | 0.993 | Probably Damaging | -1.35 | Pathogenic | 0.02 | Affected | 0.2147 | 0.4776 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1909T>C | S637P 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S637P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, premPS, polyPhen‑2 HumVar, and FATHMM, while pathogenic calls arise from FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments give a pathogenic signal: the SGM Consensus predicts likely pathogenic, Foldetta predicts destabilizing pathogenic effects, whereas AlphaMissense‑Optimized remains uncertain. Overall, the balance of evidence favors a pathogenic interpretation, and this conclusion does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -11.455 | Likely Pathogenic | 0.793 | Likely Pathogenic | Ambiguous | 6.73 | Destabilizing | 0.1 | 6.36 | Destabilizing | 6.55 | Destabilizing | 0.44 | Likely Benign | 0.192 | Likely Benign | -3.12 | Deleterious | 0.946 | Possibly Damaging | 0.360 | Benign | 3.36 | Benign | 0.03 | Affected | 0.2374 | 0.4094 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.1921T>C | S641P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN and SIFT. The remaining tools (FoldX, Foldetta, premPS, AlphaMissense‑Default) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning toward benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign based on current computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.907 | Likely Benign | 0.378 | Ambiguous | Likely Benign | 1.73 | Ambiguous | 1.3 | 0.07 | Likely Benign | 0.90 | Ambiguous | 0.59 | Ambiguous | 0.205 | Likely Benign | -3.05 | Deleterious | 0.000 | Benign | 0.000 | Benign | 3.34 | Benign | 0.04 | Affected | 0.2289 | 0.5791 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.1975T>C | S659P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are SGM‑Consensus, Rosetta, PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Tools with uncertain or inconclusive results—FoldX, premPS, and Foldetta—are treated as unavailable. High‑accuracy methods give mixed signals: AlphaMissense‑Optimized reports a benign change, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta’s stability assessment is uncertain. Overall, the balance of evidence leans toward a pathogenic effect, but the presence of a strong benign prediction from AlphaMissense‑Optimized and the lack of ClinVar annotation means the variant’s clinical significance remains uncertain and does not contradict existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -10.461 | Likely Pathogenic | 0.609 | Likely Pathogenic | Likely Benign | -0.73 | Ambiguous | 0.3 | 2.98 | Destabilizing | 1.13 | Ambiguous | 0.73 | Ambiguous | 0.224 | Likely Benign | -3.26 | Deleterious | 0.932 | Possibly Damaging | 0.245 | Benign | 3.39 | Benign | 0.18 | Tolerated | 0.2207 | 0.5553 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.19T>C | S7P 2D AIThe SynGAP1 missense variant S7P is reported in gnomAD (ID 6‑33420283‑T‑C) but has no ClinVar entry. In silico prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign status. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority‑vote) is benign; Foldetta results are unavailable. Overall, the consensus of the majority of tools, including the high‑accuracy methods, points to a benign effect. This prediction is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | 6-33420283-T-C | -3.798 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 0.210 | Likely Benign | -0.23 | Neutral | 0.267 | Benign | 0.029 | Benign | 4.07 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2474 | 0.4925 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||
| c.2002T>C | S668P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668P has no ClinVar entry and is not reported in gnomAD. Prediction tools largely agree on a deleterious effect: FATHMM is the only benign predictor, while the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify it as pathogenic or likely pathogenic. The premPS score is uncertain and therefore not used as evidence. High‑accuracy methods give consistent results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -13.452 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 6.40 | Destabilizing | 1.1 | 10.90 | Destabilizing | 8.65 | Destabilizing | 0.61 | Ambiguous | 0.612 | Likely Pathogenic | -4.82 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.16 | Benign | 0.02 | Affected | 0.1979 | 0.5137 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.2068T>C | S690P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690P is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools (FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) all predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Pathogenic”; and Foldetta, which integrates FoldX‑MD and Rosetta stability predictions, also classifies the variant as pathogenic. Overall, the preponderance of evidence from multiple independent predictors indicates that the variant is most likely pathogenic, a conclusion that does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | Uncertain | 1 | -14.568 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 4.84 | Destabilizing | 0.3 | 4.40 | Destabilizing | 4.62 | Destabilizing | 1.42 | Destabilizing | 0.431 | Likely Benign | -4.77 | Deleterious | 0.998 | Probably Damaging | 0.790 | Possibly Damaging | 3.44 | Benign | 0.01 | Affected | 3.42 | 17 | 0.1787 | 0.4050 | 1 | -1 | -0.8 | 10.04 | 207.5 | 15.1 | 0.1 | 0.0 | -0.1 | 0.2 | X | X | Potentially Pathogenic | The hydroxyl side chain of Ser690, located in an α-helix (res. Leu696-Leu685), forms a hydrogen bond with the backbone carbonyl group of Ser410 in an anti-parallel β-sheet of the C2 domain (res. Ile411-Ala399). In the variant simulations, the pyrrolidine side chain of Pro690 cannot form hydrogen bonds with the C2 domain residue, resulting in the loss of this inter-domain connection. Additionally, prolines lack a free amide group necessary for hydrogen bonding with the carbonyl group of Gly686, introducing a slight bend in the α-helix and compromising its integrity. | |||||||||||||||
| c.2254T>C | S752P 2D AIThe SynGAP1 missense variant S752P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for S752P, 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 | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -3.491 | Likely Benign | 0.158 | Likely Benign | Likely Benign | 0.183 | Likely Benign | -1.09 | Neutral | 0.998 | Probably Damaging | 0.912 | Probably Damaging | 1.51 | Pathogenic | 0.02 | Affected | 0.2288 | 0.5882 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.226T>C | S76P 2D AIThe SynGAP1 missense variant S76P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for S76P, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | -3.833 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -1.64 | Neutral | 0.909 | Possibly Damaging | 0.665 | Possibly Damaging | 3.77 | Benign | 0.00 | Affected | 0.1790 | 0.4138 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2296T>C | S766P 2D AIThe SynGAP1 missense variant S766P is reported in gnomAD (ID 6‑33442454‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while SIFT uniquely predicts it as pathogenic. The remaining tools, ESM1b and AlphaMissense‑Default, are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta stability analysis is unavailable. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | 6-33442454-T-C | 1 | 1.28e-6 | -7.343 | In-Between | 0.374 | Ambiguous | Likely Benign | 0.193 | Likely Benign | -0.91 | Neutral | 0.006 | Benign | 0.013 | Benign | 4.07 | Benign | 0.01 | Affected | 3.64 | 6 | 0.2216 | 0.5862 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.2311T>C | S771P 2D AIThe SynGAP1 missense variant S771P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -5.045 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.180 | Likely Benign | -1.32 | Neutral | 0.901 | Possibly Damaging | 0.692 | Possibly Damaging | 4.03 | Benign | 0.19 | Tolerated | 0.2194 | 0.5515 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2338T>C | S780P 2D AIThe SynGAP1 missense variant S780P is reported in gnomAD (ID 6‑33442890‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. 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, SGM‑Consensus is likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | 6-33442890-T-C | 1 | 6.22e-7 | -6.055 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 0.088 | Likely Benign | -1.11 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.64 | Benign | 0.30 | Tolerated | 3.64 | 6 | 0.2086 | 0.6171 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.2362T>C | S788P 2D AIThe SynGAP1 missense variant S788P is catalogued in gnomAD (ID 6‑33442914‑T‑C) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The AlphaMissense‑Default score is uncertain. A consensus derived from the SGM framework (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic verdict. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is unavailable for this residue. Taken together, the preponderance of evidence from standard predictors and the SGM consensus points to a likely pathogenic effect, which does not contradict any existing ClinVar annotation because none is present. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | 6-33442914-T-C | -1.857 | Likely Benign | 0.435 | Ambiguous | Likely Benign | 0.236 | Likely Benign | -3.91 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.51 | Pathogenic | 0.01 | Affected | 3.64 | 6 | 0.2338 | 0.5537 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||
| c.2446T>C | S816P 2D AIThe SynGAP1 missense variant S816P 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 majority of other predictors (polyPhen‑2 HumDiv and HumVar) suggest pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign and the SGM‑Consensus likewise indicates Likely Benign; Foldetta data are unavailable. Overall, the preponderance of evidence points to a benign effect for S816P, and this conclusion is not in conflict with ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.662 | Likely Benign | 0.510 | Ambiguous | Likely Benign | 0.160 | Likely Benign | -0.26 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.66 | Benign | 0.45 | Tolerated | 0.2298 | 0.5102 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2449T>C | S817P 2D AIThe SynGAP1 missense variant S817P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, ESM1b, and AlphaMissense‑Optimized, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Pathogenic, and Foldetta results are unavailable. Overall, the majority of tools and the consensus score indicate a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -4.633 | Likely Benign | 0.724 | Likely Pathogenic | Likely Benign | 0.201 | Likely Benign | -3.26 | Deleterious | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.39 | Pathogenic | 0.00 | Affected | 0.2272 | 0.6023 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2473T>C | S825P 2D AIThe SynGAP1 missense variant S825P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, and the SGM‑Consensus is labeled Likely Pathogenic. Foldetta results are not available for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that S825P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.675549 | Disordered | 0.618614 | Binding | 0.384 | 0.886 | 0.750 | -3.227 | Likely Benign | 0.959 | Likely Pathogenic | Likely Pathogenic | 0.285 | Likely Benign | -3.12 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.94 | Pathogenic | 0.02 | Affected | 0.2060 | 0.5998 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2524T>C | S842P 2D AIThe SynGAP1 missense variant S842P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity largely agree: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict a deleterious effect. Only REVEL classifies the variant as benign. High‑accuracy assessments further support a pathogenic interpretation: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus indicates “Likely Pathogenic.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the consensus of the majority of tools, including the high‑accuracy predictors, indicates that S842P is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.617281 | Binding | 0.274 | 0.861 | 0.250 | -13.890 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.309 | Likely Benign | -3.43 | Deleterious | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 1.99 | Pathogenic | 0.00 | Affected | 0.1494 | 0.5342 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2581T>C | S861P 2D AIThe SynGAP1 missense variant S861P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for S861P, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.557691 | Disordered | 0.540903 | Binding | 0.285 | 0.797 | 0.250 | -4.256 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.65 | Neutral | 0.960 | Probably Damaging | 0.761 | Possibly Damaging | 3.93 | Benign | 0.13 | Tolerated | 0.1830 | 0.6011 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.259T>C | S87P 2D AIThe SynGAP1 missense variant S87P is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 vs 2), and Foldetta results are unavailable. Based on the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.690604 | Disordered | 0.550904 | Binding | 0.302 | 0.878 | 0.500 | -8.566 | Likely Pathogenic | 0.985 | Likely Pathogenic | Likely Pathogenic | 0.073 | Likely Benign | -2.04 | Neutral | 0.676 | Possibly Damaging | 0.307 | Benign | 3.75 | Benign | 0.00 | Affected | 0.1639 | 0.4260 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||||
| c.2614T>C | S872P 2D AIThe SynGAP1 missense variant S872P 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‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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 predicts Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence indicates that S872P 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 | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -4.291 | Likely Benign | 0.273 | Likely Benign | Likely Benign | 0.187 | Likely Benign | -1.91 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.59 | Benign | 0.13 | Tolerated | 0.2321 | 0.5581 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>C | S876P 2D AIThe SynGAP1 missense variant S876P 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 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 indicates that S876P 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 | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -5.002 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.171 | Likely Benign | -2.04 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.56 | Benign | 0.35 | Tolerated | 0.1979 | 0.6928 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2674T>C | S892P 2D AIThe SynGAP1 missense variant S892P is reported in gnomAD (ID 6‑33443226‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | 6-33443226-T-C | 1 | 6.20e-7 | -3.247 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.87 | Neutral | 0.057 | Benign | 0.047 | Benign | 2.60 | Benign | 0.01 | Affected | 4.32 | 4 | 0.2230 | 0.5251 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.2689T>C | S897P 2D AIThe SynGAP1 missense variant S897P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.699094 | Disordered | 0.418474 | Uncertain | 0.292 | 0.928 | 0.500 | -4.088 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.21 | Neutral | 0.990 | Probably Damaging | 0.856 | Possibly Damaging | 2.64 | Benign | 0.04 | Affected | 0.2014 | 0.5933 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2692T>C | S898P 2D AIThe SynGAP1 missense variant S898P 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. 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 not available. Overall, the majority of predictions (six benign vs. four pathogenic) support a benign classification. There is no ClinVar entry to contradict this assessment, so 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 | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -4.192 | Likely Benign | 0.307 | Likely Benign | Likely Benign | 0.149 | Likely Benign | 0.44 | Neutral | 0.998 | Probably Damaging | 0.939 | Probably Damaging | 2.45 | Pathogenic | 0.01 | Affected | 0.2400 | 0.6555 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2776T>C | S926P 2D AIThe SynGAP1 missense variant S926P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic outcome: PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), yielding a Likely Pathogenic classification. AlphaMissense‑Optimized is uncertain, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a pathogenic effect for S926P. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -3.873 | Likely Benign | 0.916 | Likely Pathogenic | Ambiguous | 0.424 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.51 | Pathogenic | 0.00 | Affected | 0.1738 | 0.5058 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2863T>C | S955P 2D AIThe SynGAP1 missense variant S955P is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443415‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Tools that predict a pathogenic effect are SIFT and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | Uncertain | 1 | 6-33443415-T-C | 3 | 1.86e-6 | -2.584 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.098 | Likely Benign | -0.75 | Neutral | 0.001 | Benign | 0.004 | Benign | 2.33 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.2629 | 0.5537 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||
| c.2866T>C | S956P 2D AIThe SynGAP1 missense variant S956P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -3.526 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.157 | Likely Benign | -0.55 | Neutral | 0.000 | Benign | 0.001 | Benign | 1.95 | Pathogenic | 0.05 | Affected | 0.2670 | 0.5337 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2965T>C | S989P 2D AIThe SynGAP1 missense variant S989P is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are unavailable. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -2.688 | Likely Benign | 0.209 | Likely Benign | Likely Benign | 0.147 | Likely Benign | -2.48 | Neutral | 0.010 | Benign | 0.015 | Benign | 2.67 | Benign | 0.00 | Affected | 0.1690 | 0.4941 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2968T>C | S990P 2D AIThe SynGAP1 missense variant S990P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of any ClinVar pathogenic annotation. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -3.150 | Likely Benign | 0.122 | Likely Benign | Likely Benign | 0.117 | Likely Benign | -1.95 | Neutral | 0.586 | Possibly Damaging | 0.377 | Benign | 2.74 | Benign | 0.01 | Affected | 0.1910 | 0.5345 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.2995T>C | S999P 2D AIThe SynGAP1 missense variant S999P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for S999P, 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 | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -2.279 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.111 | Likely Benign | -1.05 | Neutral | 0.966 | Probably Damaging | 0.773 | Possibly Damaging | 2.65 | Benign | 0.04 | Affected | 0.1963 | 0.6268 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3037T>C | S1013P 2D AIThe SynGAP1 missense variant S1013P is reported in gnomAD (ID 6‑33443589‑T‑C) 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 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 is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | 6-33443589-T-C | 2 | 1.24e-6 | -2.563 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -1.27 | Neutral | 0.453 | Possibly Damaging | 0.150 | Benign | 2.66 | Benign | 0.15 | Tolerated | 3.77 | 5 | 0.2338 | 0.5430 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.3067T>C | S1023P 2D AIThe SynGAP1 missense variant S1023P is reported in gnomAD (ID 6‑33443619‑T‑C) but has no ClinVar entry (ClinVar status: not reported). Functional prediction tools are split: benign calls come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized, while pathogenic calls come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (two benign, two pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, SGM Consensus remains inconclusive, and Foldetta (combining FoldX‑MD and Rosetta) has no available result. Overall, the majority of standard predictors lean toward pathogenicity, whereas the few high‑accuracy tools do not support a pathogenic verdict. Thus, the variant is most likely pathogenic based on the aggregate predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | 6-33443619-T-C | 2 | 1.24e-6 | -5.634 | Likely Benign | 0.679 | Likely Pathogenic | Likely Benign | 0.146 | Likely Benign | -2.11 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.43 | Pathogenic | 0.02 | Affected | 3.77 | 5 | 0.1818 | 0.4616 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3097T>C | S1033P 2D AIThe SynGAP1 missense variant S1033P is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. 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: AlphaMissense‑Optimized predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Foldetta results are not available, so they do not influence the overall assessment. Based on the consensus of all available predictions, the variant is most likely benign, 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 | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -2.046 | Likely Benign | 0.268 | Likely Benign | Likely Benign | 0.068 | Likely Benign | 0.05 | Neutral | 0.002 | Benign | 0.005 | Benign | 2.68 | Benign | 0.27 | Tolerated | 0.1889 | 0.5486 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3139T>C | S1047P 2D AIThe SynGAP1 missense variant S1047P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely benign. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions points to a benign impact, and this is consistent with the lack of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | -2.415 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.52 | Neutral | 0.001 | Benign | 0.001 | Benign | 2.62 | Benign | 0.03 | Affected | 0.2373 | 0.5656 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.313T>C | S105P 2D AIThe SynGAP1 missense variant S105P is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only two tools—polyPhen‑2 HumDiv and SIFT—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 vote) also indicates likely benign. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | Uncertain | 1 | -3.631 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.204 | Likely Benign | 0.03 | Neutral | 0.808 | Possibly Damaging | 0.212 | Benign | 4.00 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2236 | 0.4584 | -1 | 1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.3217T>C | S1073P 2D AIThe SynGAP1 missense variant S1073P is reported in gnomAD (variant ID 6‑33443769‑T‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for S1073P, 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 | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | 6-33443769-T-C | 1 | 6.23e-7 | -4.520 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.082 | Likely Benign | -0.76 | Neutral | 0.006 | Benign | 0.008 | Benign | 3.85 | Benign | 0.01 | Affected | 3.77 | 5 | 0.2243 | 0.5900 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.3259T>C | S1087P 2D AIThe SynGAP1 missense variant S1087P is reported in gnomAD (ID 6‑33443811‑T‑C) and 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 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 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 | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | 6-33443811-T-C | 1 | 6.34e-7 | -2.946 | Likely Benign | 0.133 | Likely Benign | Likely Benign | 0.135 | Likely Benign | -1.92 | Neutral | 0.006 | Benign | 0.008 | Benign | 2.56 | Benign | 0.12 | Tolerated | 3.77 | 5 | 0.1803 | 0.5700 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||
| c.3280T>C | S1094P 2D AIThe SynGAP1 missense variant S1094P 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools 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 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 for S1094P, 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 | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -2.430 | Likely Benign | 0.285 | Likely Benign | Likely Benign | 0.124 | Likely Benign | -1.31 | Neutral | 0.990 | Probably Damaging | 0.798 | Possibly Damaging | 2.46 | Pathogenic | 0.13 | Tolerated | 0.2322 | 0.6099 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3394T>C | S1132P 2D AIThe SynGAP1 missense variant S1132P is listed in ClinVar with an uncertain significance (ClinVar ID 1341927.0) and is present in the gnomAD database (gnomAD ID 6‑33443946‑T‑C). All available in‑silico predictors uniformly classify the substitution as benign: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or likely benign outcomes. No tool in the dataset 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, 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 classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | Conflicting | 3 | 6-33443946-T-C | 1 | 6.74e-7 | -1.423 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.301 | Likely Benign | 0.38 | Neutral | 0.003 | Benign | 0.006 | Benign | 5.40 | Benign | 0.28 | Tolerated | 4.32 | 4 | 0.2081 | 0.5700 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||
| c.3412T>C | S1138P 2D AIThe SynGAP1 missense variant S1138P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | -5.023 | Likely Benign | 0.187 | Likely Benign | Likely Benign | 0.456 | Likely Benign | -1.21 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.41 | Benign | 0.10 | Tolerated | 0.2297 | 0.5856 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3424T>C | S1142P 2D AIThe SynGAP1 missense variant S1142P is listed in ClinVar (ID 2747352.0) as Benign and is present in gnomAD (variant ID 6‑33444459‑T‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta, 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, 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 | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | Likely Benign | 1 | 6-33444459-T-C | 1 | 6.20e-7 | -2.713 | Likely Benign | 0.222 | Likely Benign | Likely Benign | 0.107 | Likely Benign | -2.19 | Neutral | 0.918 | Possibly Damaging | 0.761 | Possibly Damaging | 2.64 | Benign | 0.00 | Affected | 4.32 | 4 | 0.2080 | 0.5618 | -1 | 1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||
| c.3451T>C | S1151P 2D AIThe SynGAP1 missense variant S1151P 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 this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are not available. Overall, the consensus of the available predictions indicates that the variant 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 | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -3.031 | Likely Benign | 0.298 | Likely Benign | Likely Benign | 0.123 | Likely Benign | -1.47 | Neutral | 0.995 | Probably Damaging | 0.892 | Possibly Damaging | 2.67 | Benign | 0.11 | Tolerated | 0.1953 | 0.5320 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3475T>C | S1159P 2D AIThe SynGAP1 missense variant S1159P is not reported in ClinVar and has no gnomAD entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and the SGM‑Consensus score, which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus (majority vote) is benign. No Foldetta stability prediction is available for this residue. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -3.656 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -2.06 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.64 | Benign | 0.14 | Tolerated | 0.1807 | 0.5111 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.3493T>C | S1165P 2D AIThe SynGAP1 missense variant S1165P 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 those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 Pathogenic, whereas the SGM‑Consensus remains Likely Benign; Foldetta results are unavailable. Overall, the majority of tools (six benign vs. four pathogenic) indicate that the variant is most likely benign. This conclusion is not contradicted by ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.476 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.147 | Likely Benign | -1.87 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.55 | Benign | 0.23 | Tolerated | 0.2295 | 0.4930 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| 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.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.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.3634T>C | S1212P 2D AIThe SynGAP1 missense variant S1212P is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that classify the variant as benign include only REVEL, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict it to be pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic effect. High‑accuracy assessments further support this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus likewise reports 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 computational evidence points to the variant being most likely pathogenic, and this conclusion does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.566480 | Disordered | 0.548409 | Binding | 0.852 | 0.565 | 0.500 | -13.336 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.239 | Likely Benign | -3.79 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 0.1585 | 0.4370 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||||||||||
| 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.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.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.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.436T>C | S146P 2D AIThe SynGAP1 missense variant S146P is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions arise from PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments reinforce the pathogenic signal: AlphaMissense‑Optimized predicts pathogenic, and the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely pathogenic. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for S146P, and this conclusion is not contradicted by ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.541878 | Disordered | 0.508612 | Binding | 0.349 | 0.837 | 0.625 | -13.292 | Likely Pathogenic | 0.976 | Likely Pathogenic | Likely Pathogenic | 0.215 | Likely Benign | -3.11 | Deleterious | 0.392 | Benign | 0.230 | Benign | 3.60 | Benign | 0.00 | Affected | 0.1934 | 0.4627 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.49T>C | S17P 2D AIThe SynGAP1 missense variant S17P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign effect. AlphaMissense‑Optimized independently scores the variant as 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. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -3.251 | Likely Benign | 0.256 | Likely Benign | Likely Benign | 0.210 | Likely Benign | -0.65 | Neutral | 0.212 | Benign | 0.010 | Benign | 4.01 | Benign | 0.00 | Affected | 0.2406 | 0.6473 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.538T>C | S180P 2D AIThe SynGAP1 missense variant S180P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas those that predict a pathogenic effect comprise PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM‑Consensus as Likely Pathogenic; the Foldetta protein‑folding stability analysis is unavailable. Based on the preponderance of pathogenic predictions and the high‑accuracy consensus, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -14.574 | Likely Pathogenic | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.225 | Likely Benign | -3.19 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 3.81 | Benign | 0.01 | Affected | 0.1916 | 0.4735 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.544T>C | S182P 2D AIThe SynGAP1 missense variant S182P is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas pathogenic predictions are made by PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic, and the SGM‑Consensus (majority of the four high‑accuracy tools) also indicates pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -13.362 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.279 | Likely Benign | -3.71 | Deleterious | 0.838 | Possibly Damaging | 0.367 | Benign | 3.67 | Benign | 0.00 | Affected | 0.2438 | 0.5030 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.553T>C | S185P 2D AIThe SynGAP1 missense variant S185P is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect are REVEL and FATHMM, whereas the remaining tools—PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. The Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the preponderance of evidence from both general and high‑accuracy predictors indicates that the S185P variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -15.129 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.285 | Likely Benign | -4.02 | Deleterious | 0.940 | Possibly Damaging | 0.462 | Possibly Damaging | 3.56 | Benign | 0.00 | Affected | 0.2156 | 0.5242 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||||||
| c.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.634T>C | S212P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S212P is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX and FATHMM, whereas the remaining tools—REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus—predict it to be pathogenic. High‑accuracy methods give consistent pathogenic results: AlphaMissense‑Optimized scores it as pathogenic; the SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates pathogenicity; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a destabilizing, pathogenic effect. With the overwhelming majority of tools supporting pathogenicity and no ClinVar entry to contradict, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -13.051 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.02 | Likely Benign | 0.9 | 6.30 | Destabilizing | 3.16 | Destabilizing | 0.90 | Ambiguous | 0.809 | Likely Pathogenic | -4.13 | Deleterious | 0.995 | Probably Damaging | 0.979 | Probably Damaging | 5.75 | Benign | 0.01 | Affected | 0.1859 | 0.5679 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| 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.676T>C | S226P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226P is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools (REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus) all predict a pathogenic or likely pathogenic outcome. Uncertain results are reported by FoldX, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic effect. Overall, the preponderance of evidence indicates that S226P 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 | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -11.030 | Likely Pathogenic | 0.933 | Likely Pathogenic | Ambiguous | 1.51 | Ambiguous | 1.1 | 5.29 | Destabilizing | 3.40 | Destabilizing | 0.57 | Ambiguous | 0.776 | Likely Pathogenic | -3.22 | Deleterious | 0.971 | Probably Damaging | 0.543 | Possibly Damaging | 5.74 | Benign | 0.04 | Affected | 0.2837 | 0.7038 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||
| c.703T>C | S235P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S235P is listed in ClinVar as Pathogenic (ClinVar ID 1067856.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect are polyPhen‑2 HumVar and FATHMM; all other evaluated algorithms—including REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a pathogenic verdict; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports pathogenic. No predictions or stability results are missing or inconclusive. **Based on the collective predictions, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.250310 | Structured | 0.319150 | Uncertain | 0.743 | 0.331 | 0.000 | Likely Pathogenic | 1 | -14.857 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.02 | Destabilizing | 0.1 | 6.91 | Destabilizing | 5.47 | Destabilizing | 1.23 | Destabilizing | 0.870 | Likely Pathogenic | -4.24 | Deleterious | 0.917 | Possibly Damaging | 0.446 | Benign | 5.47 | Benign | 0.01 | Affected | 3.40 | 14 | 0.2432 | 0.5307 | 1 | -1 | -0.8 | 10.04 | 201.5 | 17.0 | 0.1 | 0.0 | -0.6 | 0.0 | X | Potentially Pathogenic | In the WT, the hydroxyl group of Ser235, located in a β-α loop between an anti-parallel β sheet strand (res. Gly227-Phe231) and an α helix (residues Ala236-Val250), forms hydrogen bonds with the GAP domain loop residue Glu680 and with the backbone amide groups of Ala237 and Glu238 from the α helix. In the variant simulations, the pyrrolidine ring of Pro235 cannot stabilize the α helix end or maintain tertiary bonding interactions between the PH and GAP domains via hydrogen bonding as effectively as serine. | ||||||||||||||||
| c.82T>C | S28P 2D AIThe SynGAP1 missense variant S28P is listed in ClinVar (ID 1500161.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign, while only SIFT indicates a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta stability analysis is unavailable. Overall, the collective evidence points to a benign classification for S28P, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.438157 | Uncertain | 0.354 | 0.884 | 0.125 | Uncertain | 1 | -3.309 | Likely Benign | 0.051 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 1.37 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.53 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2432 | 0.5499 | 1 | -1 | -0.8 | 10.04 | |||||||||||||||||||||||||||||||||||
| c.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.898T>C | S300P 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S300P is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. The remaining tools—FoldX, Foldetta, and ESM1b—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, while Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.356642 | Structured | 0.256848 | Uncertain | 0.742 | 0.280 | 0.375 | -7.379 | In-Between | 0.110 | Likely Benign | Likely Benign | 1.24 | Ambiguous | 1.0 | 0.06 | Likely Benign | 0.65 | Ambiguous | 0.50 | Likely Benign | 0.086 | Likely Benign | -2.46 | Neutral | 0.784 | Possibly Damaging | 0.390 | Benign | 1.54 | Pathogenic | 0.02 | Affected | 0.2192 | 0.5585 | 1 | -1 | -0.8 | 10.04 | ||||||||||||||||||||||||||||||
| c.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.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.1040C>T | T347I 2D  3DClick to see structure in 3D Viewer AISynGAP1 T347I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that provide definitive calls cluster into two groups: benign predictions come from REVEL, premPS, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. Tools with inconclusive outputs (FoldX, Rosetta, Foldetta, AlphaMissense‑Default) are treated as unavailable. High‑accuracy assessments further split the evidence: AlphaMissense‑Optimized predicts benign, while the SGM consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—predicts pathogenic; Foldetta remains uncertain. Consequently, the variant’s pathogenicity is ambiguous, with an equal number of strong benign and pathogenic calls and no consensus from the most reliable methods. The variant is therefore most likely uncertain, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | -10.148 | Likely Pathogenic | 0.387 | Ambiguous | Likely Benign | -0.79 | Ambiguous | 0.1 | -0.94 | Ambiguous | -0.87 | Ambiguous | 0.29 | Likely Benign | 0.079 | Likely Benign | -3.12 | Deleterious | 0.627 | Possibly Damaging | 0.139 | Benign | 1.70 | Pathogenic | 0.08 | Tolerated | 0.0885 | 0.6298 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1055C>T | T352I 2D AISynGAP1 T352I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, Rosetta, premPS, SIFT, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar. Those that predict pathogenicity are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, ESM1b, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus majority vote (AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) as benign. With seven benign versus five pathogenic predictions and two high‑accuracy benign versus one pathogenic, the evidence leans toward a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | -8.023 | Likely Pathogenic | 0.321 | Likely Benign | Likely Benign | -0.54 | Ambiguous | 0.7 | 0.43 | Likely Benign | -0.06 | Likely Benign | 0.09 | Likely Benign | 0.099 | Likely Benign | -3.02 | Deleterious | 0.627 | Possibly Damaging | 0.196 | Benign | 1.67 | Pathogenic | 0.14 | Tolerated | 0.1009 | 0.6484 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1076C>T | T359I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T359I is reported in gnomAD (variant ID 6‑33437981‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. Uncertain results are reported for FoldX, Rosetta, Foldetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as Uncertain. Overall, the majority of evidence points to a benign effect. There is no ClinVar status to contradict this conclusion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.281712 | Structured | 0.414952 | Uncertain | 0.939 | 0.480 | 0.250 | 6-33437981-C-T | 1 | 6.22e-7 | -2.594 | Likely Benign | 0.181 | Likely Benign | Likely Benign | -0.66 | Ambiguous | 0.1 | -0.64 | Ambiguous | -0.65 | Ambiguous | -0.63 | Ambiguous | 0.085 | Likely Benign | 0.77 | Neutral | 0.070 | Benign | 0.006 | Benign | 1.80 | Pathogenic | 0.23 | Tolerated | 3.38 | 24 | 0.1123 | 0.5921 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| c.1097C>T | T366I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T366I is reported in gnomAD (6‑33438002‑C‑T) and has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. No other tools provide conclusive evidence for pathogenicity. **Based on the aggregate predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | 6-33438002-C-T | 1 | 6.20e-7 | -4.921 | Likely Benign | 0.279 | Likely Benign | Likely Benign | -0.62 | Ambiguous | 0.1 | -0.31 | Likely Benign | -0.47 | Likely Benign | -0.14 | Likely Benign | 0.058 | Likely Benign | -1.22 | Neutral | 0.002 | Benign | 0.001 | Benign | 1.77 | Pathogenic | 0.26 | Tolerated | 3.38 | 23 | 0.1062 | 0.6215 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| c.1106C>T | T369I 2D AIThe SynGAP1 missense variant T369I is not 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, providing no definitive evidence. 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; there is no conflict with ClinVar status, which contains no entry for this variant. Thus, the variant is most likely benign based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.468512 | Structured | 0.437011 | Uncertain | 0.417 | 0.707 | 0.500 | -6.759 | Likely Benign | 0.289 | Likely Benign | Likely Benign | 0.60 | Ambiguous | 0.8 | 1.41 | Ambiguous | 1.01 | Ambiguous | -0.08 | Likely Benign | 0.078 | Likely Benign | -2.37 | Neutral | 0.396 | Benign | 0.142 | Benign | 1.72 | Pathogenic | 0.13 | Tolerated | 0.1106 | 0.7207 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1223C>T | T408I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T408I missense variant is not reported in ClinVar (ClinVar ID None) but is present in gnomAD (ID 6‑33438128‑C‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and ESM1b. Tools with uncertain or mixed outputs are AlphaMissense‑Default and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points toward a benign effect, and this conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.161087 | Structured | 0.370935 | Uncertain | 0.907 | 0.239 | 0.000 | 6-33438128-C-T | 1 | 6.19e-7 | -10.023 | Likely Pathogenic | 0.542 | Ambiguous | Likely Benign | -0.16 | Likely Benign | 0.1 | -0.67 | Ambiguous | -0.42 | Likely Benign | 0.38 | Likely Benign | 0.131 | Likely Benign | -4.53 | Deleterious | 0.976 | Probably Damaging | 0.607 | Possibly Damaging | 4.08 | Benign | 0.05 | Affected | 3.38 | 28 | 0.0905 | 0.6700 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.1274C>T | T425I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425I is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM; pathogenic predictions come from SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates likely pathogenic, whereas Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the balance of evidence slightly favors a pathogenic interpretation, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -10.443 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | -0.04 | Likely Benign | 0.2 | 0.07 | Likely Benign | 0.02 | Likely Benign | 0.30 | Likely Benign | 0.268 | Likely Benign | -5.30 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.44 | Benign | 0.06 | Tolerated | 0.0827 | 0.4023 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1373C>T | T458I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T458I missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM. Those that predict a pathogenic impact are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (seven versus six) and the two high‑accuracy pathogenic predictions suggest the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar classification is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.294848 | Uncertain | 0.915 | 0.144 | 0.000 | -9.436 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | -0.40 | Likely Benign | 0.1 | 0.29 | Likely Benign | -0.06 | Likely Benign | 0.50 | Likely Benign | 0.337 | Likely Benign | -4.76 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.40 | Benign | 0.09 | Tolerated | 0.0724 | 0.6128 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1472C>T | T491I 2D AIThe SynGAP1 missense variant T491I is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include only premPS; all other evaluated algorithms (SGM‑Consensus, REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact, while FoldX is uncertain and therefore not counted in either group. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized reports a pathogenic change, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. Based on the collective predictions, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -12.525 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.48 | Ambiguous | 1.8 | 3.73 | Destabilizing | 2.61 | Destabilizing | 0.49 | Likely Benign | 0.915 | Likely Pathogenic | -5.89 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.42 | Pathogenic | 0.00 | Affected | 0.0898 | 0.4942 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1595C>T | T532I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T532I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, polyPhen‑2 HumVar, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized classifies the variant as benign, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) reports a benign effect. Overall, the balance of evidence leans toward pathogenicity, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.275179 | Structured | 0.021478 | Uncertain | 0.889 | 0.385 | 0.000 | -9.031 | Likely Pathogenic | 0.591 | Likely Pathogenic | Likely Benign | -0.11 | Likely Benign | 0.2 | 0.87 | Ambiguous | 0.38 | Likely Benign | 0.22 | Likely Benign | 0.428 | Likely Benign | -3.31 | Deleterious | 0.633 | Possibly Damaging | 0.202 | Benign | -1.31 | Pathogenic | 0.03 | Affected | 0.0713 | 0.4983 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1856C>T | T619I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that assess pathogenicity unanimously classify the variant as pathogenic: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect; the remaining tools (FoldX, Rosetta, Foldetta, premPS) return uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is uncertain. Based on the consensus of pathogenic predictions and the lack of benign evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -11.760 | Likely Pathogenic | 0.975 | Likely Pathogenic | Likely Pathogenic | -1.06 | Ambiguous | 0.1 | -1.35 | Ambiguous | -1.21 | Ambiguous | 0.58 | Ambiguous | 0.735 | Likely Pathogenic | -5.54 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.40 | Pathogenic | 0.03 | Affected | 0.0869 | 0.4377 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1865C>T | T622I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T622I is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign are Foldetta and premPS, whereas the remaining tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all predict it to be pathogenic; FoldX and Rosetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall distribution of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -13.276 | Likely Pathogenic | 0.979 | Likely Pathogenic | Likely Pathogenic | -1.47 | Ambiguous | 0.1 | 0.67 | Ambiguous | -0.40 | Likely Benign | 0.45 | Likely Benign | 0.905 | Likely Pathogenic | -5.57 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.57 | Pathogenic | 0.00 | Affected | 0.0855 | 0.4926 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1871C>T | T624I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T624I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include Rosetta, premPS, and 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 (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for T624I. This prediction is consistent with the lack of ClinVar annotation and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -10.999 | Likely Pathogenic | 0.988 | Likely Pathogenic | Likely Pathogenic | -0.74 | Ambiguous | 0.1 | -0.39 | Likely Benign | -0.57 | Ambiguous | 0.14 | Likely Benign | 0.865 | Likely Pathogenic | -5.95 | Deleterious | 1.000 | Probably Damaging | 0.972 | Probably Damaging | -1.43 | Pathogenic | 0.08 | Tolerated | 0.0728 | 0.4734 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.1919C>T | T640I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only PROVEAN predicts a pathogenic outcome. The remaining tools (FoldX, Rosetta, ESM1b, AlphaMissense‑Default, and Foldetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is unavailable due to a tie, and Foldetta also yields an uncertain stability change. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -7.256 | In-Between | 0.358 | Ambiguous | Likely Benign | 0.70 | Ambiguous | 0.1 | 0.66 | Ambiguous | 0.68 | Ambiguous | 0.28 | Likely Benign | 0.193 | Likely Benign | -2.75 | Deleterious | 0.322 | Benign | 0.022 | Benign | 3.46 | Benign | 0.12 | Tolerated | 0.1030 | 0.4793 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||
| c.2021C>T | T674I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674I is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (ID 6‑33441280‑C‑T). Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, and ESM1b (polyPhen‑2 HumVar is benign). AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic. Overall, the majority of evidence points to 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. | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | 6-33441280-C-T | 2 | 1.24e-6 | -8.951 | Likely Pathogenic | 0.522 | Ambiguous | Likely Benign | -0.05 | Likely Benign | 0.1 | 0.28 | Likely Benign | 0.12 | Likely Benign | -0.04 | Likely Benign | 0.289 | Likely Benign | -3.18 | Deleterious | 0.981 | Probably Damaging | 0.444 | Benign | 3.46 | Benign | 0.11 | Tolerated | 3.40 | 24 | 0.0898 | 0.6945 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||||
| c.2072C>T | T691I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T691I is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33441331‑C‑T). Prediction tools that agree on a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX, Foldetta, and premPS. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, while Foldetta remains uncertain. Overall, the evidence overwhelmingly indicates that T691I is most likely benign, and this conclusion does not contradict the ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.060549 | Structured | 0.271308 | Uncertain | 0.941 | 0.232 | 0.000 | 6-33441331-C-T | 1 | 6.20e-7 | -5.857 | Likely Benign | 0.202 | Likely Benign | Likely Benign | -1.08 | Ambiguous | 0.1 | -2.12 | Stabilizing | -1.60 | Ambiguous | -0.61 | Ambiguous | 0.052 | Likely Benign | -1.19 | Neutral | 0.040 | Benign | 0.003 | Benign | 3.49 | Benign | 0.34 | Tolerated | 3.43 | 14 | 0.0644 | 0.5397 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| c.2168C>T | T723I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T723I is listed in ClinVar as Benign (ClinVar ID 436924.0) and is observed in gnomAD (variant ID 6‑33441633‑C‑T). Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only SIFT classifies the change as pathogenic. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, the SGM Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates a benign impact. No prediction or stability result is missing or inconclusive. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.476583 | Structured | 0.458243 | Uncertain | 0.945 | 0.447 | 0.375 | Likely Benign | 1 | 6-33441633-C-T | 2 | 1.24e-6 | -2.591 | Likely Benign | 0.120 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.0 | -0.20 | Likely Benign | -0.30 | Likely Benign | 0.26 | Likely Benign | 0.045 | Likely Benign | -2.09 | Neutral | 0.088 | Benign | 0.030 | Benign | 3.39 | Benign | 0.03 | Affected | 3.50 | 8 | 0.0708 | 0.5803 | 0 | -1 | 5.2 | 12.05 | 252.3 | -31.6 | 0.0 | 0.0 | -0.2 | 0.2 | X | Uncertain | The hydroxyl group of Thr723, located on the outer surface of an α-helix (res. Leu714-Arg726), continuously forms hydrogen bonds with the backbone carbonyl of Asn719 in the WT simulations, potentially lowering the stability of the α-helix. In the variant simulations, the sec-butyl side chain of Ile723 cannot form any hydrogen bonds, which, in theory, could increase the helix stability. However, because the model ends abruptly at the C-terminus, no definite conclusions can be drawn based on the simulations. | |||||||||||||
| c.2369C>T | T790I 2D AIThe SynGAP1 missense variant T790I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is pathogenic. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact. This conclusion does not contradict the ClinVar status, which currently has no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | -3.556 | Likely Benign | 0.482 | Ambiguous | Likely Benign | 0.190 | Likely Benign | -3.08 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.28 | Pathogenic | 0.01 | Affected | 0.0987 | 0.5431 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2483C>T | T828I 2D AISynGAP1 missense variant T828I is not 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 tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 split and therefore unavailable; Foldetta predictions are not provided. Consequently, the computational evidence is evenly divided between benign and pathogenic, with no clear direction. 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 classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.631236 | Binding | 0.321 | 0.879 | 0.500 | -4.971 | Likely Benign | 0.893 | Likely Pathogenic | Ambiguous | 0.139 | Likely Benign | -3.40 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.61 | Benign | 0.06 | Tolerated | 0.0767 | 0.5262 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||||||||
| c.254C>T | T85I 2D AIThe SynGAP1 missense variant T85I is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) predict a pathogenic impact. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic. AlphaMissense‑Optimized also predicts pathogenicity. 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 preponderance of evidence from multiple independent predictors indicates that T85I is most likely pathogenic, and this assessment does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.680603 | Disordered | 0.542004 | Binding | 0.288 | 0.888 | 0.500 | -9.310 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.113 | Likely Benign | -2.50 | Deleterious | 0.813 | Possibly Damaging | 0.072 | Benign | 3.82 | Benign | 0.00 | Affected | 0.0634 | 0.5443 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2633C>T | T878I 2D AIThe SynGAP1 missense variant T878I is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect. **Benign:** REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Optimized. **Pathogenic:** polyPhen‑2 HumDiv, SIFT. AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus itself is benign; Foldetta results are unavailable. Overall, the computational evidence overwhelmingly points to a benign effect, 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 | 0.622677 | Disordered | 0.628767 | Binding | 0.288 | 0.878 | 0.250 | -6.247 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.055 | Likely Benign | -1.99 | Neutral | 0.761 | Possibly Damaging | 0.398 | Benign | 2.63 | Benign | 0.00 | Affected | 0.0980 | 0.6502 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2735C>T | T912I 2D AIThe SynGAP1 missense variant T912I is listed in gnomAD (ID 6‑33443287‑C‑T) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and Foldetta (FoldX‑MD/Rosetta stability assessment) has no available result for this variant. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta data is missing. Overall, the majority of reliable predictors indicate a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | 6-33443287-C-T | 2 | 1.24e-6 | -4.461 | Likely Benign | 0.522 | Ambiguous | Likely Benign | 0.117 | Likely Benign | -1.27 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.95 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0945 | 0.5615 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||
| c.2738C>T | T913I 2D AIThe SynGAP1 missense variant T913I is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. 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 T913I, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.661982 | Disordered | 0.763517 | Binding | 0.339 | 0.899 | 0.375 | -4.030 | Likely Benign | 0.600 | Likely Pathogenic | Likely Benign | 0.144 | Likely Benign | -2.01 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.70 | Benign | 0.04 | Affected | 0.0903 | 0.6119 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.2924C>T | T975I 2D AIThe SynGAP1 missense variant T975I is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33443476‑C‑T). Prediction tools that agree on benign impact include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts pathogenicity. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Overall, the computational evidence overwhelmingly supports a benign effect, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | Uncertain | 1 | 6-33443476-C-T | 6 | 3.72e-6 | -3.912 | Likely Benign | 0.164 | Likely Benign | Likely Benign | 0.068 | Likely Benign | -1.66 | Neutral | 0.411 | Benign | 0.239 | Benign | 4.11 | Benign | 0.66 | Tolerated | 4.32 | 2 | 0.1107 | 0.5198 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||
| c.3044C>T | T1015I 2D AIThe SynGAP1 missense variant T1015I is not reported in ClinVar and has no entry in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, 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 further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign impact for T1015I, 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 | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -4.713 | Likely Benign | 0.326 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -2.06 | Neutral | 0.586 | Possibly Damaging | 0.172 | Benign | 2.53 | Benign | 0.07 | Tolerated | 0.1232 | 0.4871 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3053C>T | T1018I 2D AIThe SynGAP1 missense variant T1018I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33443605‑C‑T). Prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized, while those that predict pathogenicity are PROVEAN, polyPhen‑2 HumDiv, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta results are unavailable. Overall, the predictions are split, with no clear majority leaning toward either benign or pathogenic. Thus, the variant’s impact remains inconclusive, and this uncertainty aligns with ClinVar’s current “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | Uncertain | 1 | 6-33443605-C-T | 4 | 2.48e-6 | -3.264 | Likely Benign | 0.524 | Ambiguous | Likely Benign | 0.076 | Likely Benign | -2.55 | Deleterious | 0.586 | Possibly Damaging | 0.304 | Benign | 2.24 | Pathogenic | 0.01 | Affected | 3.77 | 5 | 0.1022 | 0.4776 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||
| c.3113C>T | T1038I 2D AIThe SynGAP1 T1038I missense variant has no ClinVar record and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which classifies the variant as Likely Benign. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized score is Uncertain, and the Foldetta protein‑folding stability assessment is unavailable. Overall, the balance of evidence leans toward a benign interpretation, with one high‑accuracy tool inconclusive and no conflicting ClinVar annotation. Thus, the variant is most likely benign, and there is no ClinVar status that contradicts this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -4.552 | Likely Benign | 0.877 | Likely Pathogenic | Ambiguous | 0.093 | Likely Benign | -2.02 | Neutral | 0.990 | Probably Damaging | 0.637 | Possibly Damaging | 2.69 | Benign | 0.04 | Affected | 0.1012 | 0.5036 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3230C>T | T1077I 2D AIThe SynGAP1 missense variant T1077I is listed in gnomAD (ID 6‑33443782‑C‑T) but has no ClinVar entry. 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). The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to a likely benign verdict (3 benign vs. 1 pathogenic). High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized returns an uncertain result, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this residue. Taken together, the majority of evidence points toward a benign effect. This conclusion is consistent with the absence of a ClinVar pathogenic classification, and there is no contradiction with existing database annotations. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.903857 | Disordered | 0.988141 | Binding | 0.329 | 0.892 | 0.750 | 6-33443782-C-T | 1 | 6.25e-7 | -4.710 | Likely Benign | 0.919 | Likely Pathogenic | Ambiguous | 0.155 | Likely Benign | -1.11 | Neutral | 0.970 | Probably Damaging | 0.787 | Possibly Damaging | 4.19 | Benign | 0.33 | Tolerated | 3.77 | 5 | 0.1135 | 0.5870 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||
| c.3401C>T | T1134I 2D AIThe SynGAP1 missense variant T1134I 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) 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 impact, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -4.072 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.242 | Likely Benign | -1.93 | Neutral | 0.453 | Possibly Damaging | 0.162 | Benign | 5.52 | Benign | 0.44 | Tolerated | 0.1071 | 0.5447 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3419C>T | T1140I 2D AIThe SynGAP1 missense variant T1140I 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, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports it as likely benign. Only 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 likewise indicates a likely benign effect. 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, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.926919 | Disordered | 0.708094 | Binding | 0.293 | 0.854 | 1.000 | -5.205 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -1.85 | Neutral | 0.611 | Possibly Damaging | 0.398 | Benign | 2.61 | Benign | 0.08 | Tolerated | 0.0948 | 0.4648 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3428C>T | T1143I 2D AIThe SynGAP1 missense variant T1143I is not reported in ClinVar and has no entries in gnomAD, indicating it has not been catalogued in these databases. Functional prediction tools largely agree that the substitution is benign: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify it 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 effect. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. High‑accuracy predictions from AlphaMissense‑Optimized and the SGM‑Consensus both support a benign outcome, while the absence of a Foldetta result leaves the structural impact unresolved. Overall, the majority of evidence points to a benign effect, and this conclusion is consistent with the lack of ClinVar annotation; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.722918 | Binding | 0.275 | 0.837 | 1.000 | -3.554 | Likely Benign | 0.560 | Ambiguous | Likely Benign | 0.163 | Likely Benign | -1.87 | Neutral | 0.999 | Probably Damaging | 0.966 | Probably Damaging | 2.68 | Benign | 0.10 | Tolerated | 0.1013 | 0.4274 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3440C>T | T1147I 2D AIThe SynGAP1 missense variant T1147I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.746520 | Binding | 0.345 | 0.839 | 0.875 | -3.552 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.423 | Likely Benign | -2.03 | Neutral | 0.259 | Benign | 0.059 | Benign | 5.42 | Benign | 0.01 | Affected | 0.1029 | 0.4968 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3461C>T | T1154I 2D AIThe SynGAP1 missense variant T1154I is not reported in ClinVar and has no gnomAD entry. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method that combines FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.685117 | Disordered | 0.838654 | Binding | 0.382 | 0.851 | 0.625 | -4.489 | Likely Benign | 0.999 | Likely Pathogenic | Likely Pathogenic | 0.351 | Likely Benign | -4.38 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 1.74 | Pathogenic | 0.00 | Affected | 0.0927 | 0.4956 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3689C>T | T1230I 2D AIThe SynGAP1 missense variant T1230I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of evidence (seven pathogenic vs. three benign predictions) points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.570702 | Disordered | 0.486342 | Uncertain | 0.845 | 0.543 | 0.250 | -5.661 | Likely Benign | 0.991 | Likely Pathogenic | Likely Pathogenic | 0.470 | Likely Benign | -2.63 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.43 | Benign | 0.02 | Affected | 0.0581 | 0.4898 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.3914C>T | T1305I 2D AIThe SynGAP1 missense variant T1305I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.791621 | Disordered | 0.894658 | Binding | 0.390 | 0.873 | 0.875 | -4.202 | Likely Benign | 0.221 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -1.35 | Neutral | 0.027 | Benign | 0.063 | Benign | 2.77 | Benign | 0.02 | Affected | 0.0923 | 0.6149 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||||
| c.4019C>T | T1340I 2D AIThe SynGAP1 missense variant T1340I is not reported in ClinVar (ClinVar status: “None”) but is present in gnomAD (ID 6‑33451893‑C‑T). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are PROVEAN and SIFT. AlphaMissense‑Default is uncertain, while AlphaMissense‑Optimized predicts benign. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to benign (two benign versus one pathogenic, with the uncertain result treated as unavailable). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the high‑accuracy predictions (AlphaMissense‑Optimized, SGM Consensus) both indicate a benign impact, and no evidence contradicts this assessment with the ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | 6-33451893-C-T | -3.476 | Likely Benign | 0.402 | Ambiguous | Likely Benign | 0.089 | Likely Benign | -2.57 | Deleterious | 0.334 | Benign | 0.099 | Benign | 4.08 | Benign | 0.01 | Affected | 3.77 | 5 | 0.1163 | 0.5848 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||||||||||||||||
| c.458C>T | T153I 2D AIThe SynGAP1 missense variant T153I is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Those that predict a pathogenic effect comprise polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain; 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 available predictions (5 pathogenic vs. 3 benign) indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.502105 | Binding | 0.297 | 0.818 | 0.625 | -8.809 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 0.159 | Likely Benign | -2.00 | Neutral | 0.983 | Probably Damaging | 0.725 | Possibly Damaging | 4.08 | Benign | 0.01 | Affected | 0.0839 | 0.4571 | 0 | -1 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||||||||
| 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.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.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.881C>T | T294I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on pathogenicity include REVEL, FoldX, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools with uncertain or inconclusive results are Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as pathogenic. Based on the overwhelming agreement among pathogenic predictions and the high‑accuracy tool results, the variant is most likely pathogenic. This conclusion does not contradict ClinVar status, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.316932 | Uncertain | 0.919 | 0.267 | 0.125 | -15.302 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 4.09 | Destabilizing | 0.2 | 1.33 | Ambiguous | 2.71 | Destabilizing | 0.54 | Ambiguous | 0.768 | Likely Pathogenic | -5.52 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -0.19 | Pathogenic | 0.01 | Affected | 0.0808 | 0.5485 | 0 | -1 | 5.2 | 12.05 | |||||||||||||||||||||||||||||
| c.884C>T | T295I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T295I is reported in gnomAD (ID 6‑33437789‑C‑T) but has no ClinVar entry. Functional prediction tools cluster into two consensus groups: benign predictions come from FoldX and Foldetta, while pathogenic predictions are supported by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by AlphaMissense‑Optimized, Rosetta, and premPS and are treated as inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (integrating FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points toward a pathogenic effect, with only a minority of tools indicating benign or uncertain outcomes. This prediction does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | 6-33437789-C-T | 4 | 2.48e-6 | -9.330 | Likely Pathogenic | 0.892 | Likely Pathogenic | Ambiguous | 0.21 | Likely Benign | 0.2 | 0.55 | Ambiguous | 0.38 | Likely Benign | 0.58 | Ambiguous | 0.607 | Likely Pathogenic | -4.87 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.88 | Pathogenic | 0.04 | Affected | 3.38 | 23 | 0.1025 | 0.5599 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||
| c.914C>T | T305I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T305I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33437819‑C‑T). Functional prediction tools that agree on a benign effect include REVEL, FoldX, premPS, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and Foldetta. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. The high‑accuracy AlphaMissense‑Optimized score is benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split. Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the balance of evidence from high‑confidence predictors leans toward a benign impact, and this assessment does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.359901 | Structured | 0.299706 | Uncertain | 0.872 | 0.274 | 0.125 | Uncertain | 1 | 6-33437819-C-T | 1 | 6.20e-7 | -5.222 | Likely Benign | 0.305 | Likely Benign | Likely Benign | 0.37 | Likely Benign | 0.2 | 0.58 | Ambiguous | 0.48 | Likely Benign | 0.25 | Likely Benign | 0.224 | Likely Benign | -2.90 | Deleterious | 0.997 | Probably Damaging | 0.929 | Probably Damaging | 1.70 | Pathogenic | 0.04 | Affected | 3.40 | 20 | 0.0939 | 0.5693 | -1 | 0 | 5.2 | 12.05 | |||||||||||||||||||||||
| c.95C>T | T32I 2D AIThe SynGAP1 missense variant T32I is reported in gnomAD (ID 6‑33423504‑C‑T) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus also reports likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for T32I, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | 6-33423504-C-T | 1 | 6.20e-7 | -3.689 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.57 | Neutral | 0.049 | Benign | 0.026 | Benign | 4.26 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1081 | 0.6403 | -1 | 0 | 5.2 | 12.05 | ||||||||||||||||||||||||||||||||||
| c.1040C>A | T347N 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T347N is listed in ClinVar with an uncertain significance (ClinVar ID 3672484.0) and is present in the gnomAD database (gnomAD ID 6‑33437945‑C‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Overall, the collective evidence points to a benign effect, aligning with the ClinVar designation of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.268042 | Structured | 0.349915 | Uncertain | 0.951 | 0.434 | 0.000 | Uncertain | 1 | 6-33437945-C-A | 9 | 5.58e-6 | -5.545 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.41 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.44 | Likely Benign | -0.06 | Likely Benign | 0.059 | Likely Benign | 1.96 | Neutral | 0.001 | Benign | 0.001 | Benign | 1.67 | Pathogenic | 0.60 | Tolerated | 3.37 | 25 | 0.1070 | 0.4359 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||
| c.1055C>A | T352N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T352N is listed in ClinVar as Benign (ClinVar ID 590151.0) and is present in the gnomAD database (gnomAD ID 6‑33437960‑C‑A). Across the broad panel of in‑silico predictors, 13 tools (REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) uniformly report a benign effect, whereas only FATHMM predicts pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is also benign. No predictions or stability analyses are missing or inconclusive. Overall, the computational evidence strongly supports a benign classification, consistent with the ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.137348 | Structured | 0.367886 | Uncertain | 0.926 | 0.329 | 0.000 | Likely Benign | 1 | 6-33437960-C-A | 2 | 1.24e-6 | -4.817 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.20 | Likely Benign | 0.0 | -0.04 | Likely Benign | 0.08 | Likely Benign | 0.45 | Likely Benign | 0.027 | Likely Benign | -0.92 | Neutral | 0.255 | Benign | 0.057 | Benign | 1.75 | Pathogenic | 0.19 | Tolerated | 3.37 | 25 | 0.1311 | 0.4358 | 0 | 0 | -2.8 | 13.00 | 208.4 | -14.5 | -0.2 | 0.1 | -0.1 | 0.0 | X | Potentially Benign | Thr352 is located in a short α helical section within a loop connecting two β strands (res. Gly341-Pro349, res. Thr359-Pro364) originating from two different anti-parallel β sheets of the C2 domain. In the WT simulations, the side chain hydroxyl and backbone amide groups of Thr354 form hydrogen bonds with the backbone carbonyl group of Pro349 at the end of the preceding β strand. This arrangement likely stabilizes the α helical section and aids in folding, keeping the short secondary structure element intact in the variant simulations. However, the carboxamide group of the Asn352 side chain does not form hydrogen bonds with the backbone carbonyl group of Pro349. Instead, it packs against the cyclic ring and forms hydrogen bonds with the phenol group of the Tyr363 side chain in the other β strand. | |||||||||||||
| c.1097C>A | T366N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change T366N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. Only two tools—polyPhen‑2 HumDiv and FATHMM—suggest a pathogenic effect, while premPS remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) classifies the variant as benign. Taken together, the majority of evidence supports a benign impact and is consistent with the absence of any ClinVar pathogenic annotation. 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 | C2 | 0.414856 | Structured | 0.441902 | Uncertain | 0.897 | 0.642 | 0.250 | -5.694 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.06 | Likely Benign | 0.0 | 0.36 | Likely Benign | 0.21 | Likely Benign | 0.92 | Ambiguous | 0.038 | Likely Benign | -1.72 | Neutral | 0.454 | Possibly Damaging | 0.038 | Benign | 1.72 | Pathogenic | 0.34 | Tolerated | 0.1595 | 0.4934 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1274C>A | T425N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T425N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Predictions labeled uncertain (Foldetta, premPS, AlphaMissense‑Optimized, Rosetta) are treated as unavailable. High‑accuracy assessments further indicate a likely pathogenic outcome from the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and an uncertain result from AlphaMissense‑Optimized and Foldetta. Overall, the majority of definitive predictions support a pathogenic effect, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.041405 | Structured | 0.401218 | Uncertain | 0.964 | 0.280 | 0.000 | -10.709 | Likely Pathogenic | 0.925 | Likely Pathogenic | Ambiguous | 0.19 | Likely Benign | 0.1 | 0.81 | Ambiguous | 0.50 | Ambiguous | 0.82 | Ambiguous | 0.185 | Likely Benign | -3.87 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | 3.44 | Benign | 0.04 | Affected | 0.1169 | 0.2843 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1472C>A | T491N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T491N is not reported in ClinVar and is absent from gnomAD. Prediction tools that reach consensus on pathogenicity include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized, all of which classify the substitution as pathogenic. No tool predicts a benign effect. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports it as likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain result. The remaining tools, Rosetta and Foldetta, provide inconclusive evidence. Overall, the collective evidence indicates that T491N is most likely pathogenic, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.325158 | Uncertain | 0.929 | 0.188 | 0.125 | -11.952 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.39 | Destabilizing | 0.4 | 1.44 | Ambiguous | 1.92 | Ambiguous | 1.43 | Destabilizing | 0.842 | Likely Pathogenic | -4.92 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.02 | Affected | 0.0959 | 0.2902 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1856C>A | T619N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T619N has no ClinVar entry and is not reported in gnomAD. Prediction tools that assess pathogenicity all lean toward a deleterious effect: REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. No tool predicts a benign effect. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, SGM‑Consensus is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. Based on the overall consensus of the available predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.219301 | Structured | 0.119723 | Uncertain | 0.929 | 0.237 | 0.000 | -11.796 | Likely Pathogenic | 0.900 | Likely Pathogenic | Ambiguous | 0.61 | Ambiguous | 0.1 | 0.96 | Ambiguous | 0.79 | Ambiguous | 1.23 | Destabilizing | 0.715 | Likely Pathogenic | -4.61 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.38 | Pathogenic | 0.05 | Affected | 0.0998 | 0.2690 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1865C>A | T622N 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant T622N has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect are SIFT and AlphaMissense‑Optimized, whereas a majority of tools predict a pathogenic impact: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and the SGM‑Consensus. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No prediction or stability result is missing; all available data are considered. Overall, the preponderance of evidence points to a pathogenic effect for T622N, and this conclusion is not contradicted by ClinVar status, which currently lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.071403 | Uncertain | 0.957 | 0.198 | 0.000 | -7.962 | In-Between | 0.693 | Likely Pathogenic | Likely Benign | 1.00 | Ambiguous | 0.1 | 2.37 | Destabilizing | 1.69 | Ambiguous | 0.94 | Ambiguous | 0.564 | Likely Pathogenic | -4.14 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.24 | Pathogenic | 0.13 | Tolerated | 0.0943 | 0.2848 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1871C>A | T624N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T624N is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools predict a pathogenic impact: REVEL, SIFT, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM Consensus (which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain results come from AlphaMissense‑Optimized, Rosetta, and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM Consensus as likely pathogenic, and Foldetta as benign. Overall, the balance of evidence favors a pathogenic classification for T624N, and this conclusion does not contradict any ClinVar annotation because no ClinVar status is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.137348 | Structured | 0.052894 | Uncertain | 0.962 | 0.217 | 0.000 | -14.658 | Likely Pathogenic | 0.915 | Likely Pathogenic | Ambiguous | -0.24 | Likely Benign | 0.0 | 0.87 | Ambiguous | 0.32 | Likely Benign | 0.97 | Ambiguous | 0.848 | Likely Pathogenic | -4.94 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | -1.53 | Pathogenic | 0.00 | Affected | 0.0773 | 0.2694 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.1919C>A | T640N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T640N is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. Only the protein‑stability predictors FoldX and Rosetta returned uncertain results, which are treated as unavailable evidence. High‑accuracy assessments corroborate the benign prediction: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also reports a benign effect. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.137043 | Uncertain | 0.893 | 0.284 | 0.000 | -4.258 | Likely Benign | 0.107 | Likely Benign | Likely Benign | -0.50 | Ambiguous | 0.2 | 0.53 | Ambiguous | 0.02 | Likely Benign | 0.03 | Likely Benign | 0.097 | Likely Benign | 0.51 | Neutral | 0.229 | Benign | 0.084 | Benign | 3.45 | Benign | 0.25 | Tolerated | 0.1518 | 0.4079 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.2021C>A | T674N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T674N is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic outcome; ESM1b is uncertain and does not influence the consensus. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. No contradictory evidence is present. **Based on the aggregate predictions, the variant is most likely benign, and this conclusion does not conflict with the ClinVar status.** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.129801 | Structured | 0.109297 | Uncertain | 0.521 | 0.349 | 0.000 | -7.839 | In-Between | 0.135 | Likely Benign | Likely Benign | -0.21 | Likely Benign | 0.0 | 0.15 | Likely Benign | -0.03 | Likely Benign | 0.19 | Likely Benign | 0.119 | Likely Benign | -0.71 | Neutral | 0.958 | Probably Damaging | 0.671 | Possibly Damaging | 3.44 | Benign | 0.17 | Tolerated | 0.1263 | 0.4979 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.2369C>A | T790N 2D AIThe SynGAP1 missense variant T790N is listed in ClinVar with an “Uncertain” status and is present in the gnomAD database (ID 6‑33442921‑C‑A). Prediction tools that agree on a benign effect include REVEL, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive and therefore unavailable, and Foldetta results are not reported. Overall, the majority of conventional tools (5 pathogenic vs. 4 benign) lean toward a pathogenic interpretation, while the single high‑accuracy tool suggests benign. The variant’s ClinVar status remains uncertain, so there is no contradiction with the current clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | SH3-binding motif | 0.964893 | Disordered | 0.509280 | Binding | 0.385 | 0.896 | 0.875 | Conflicting | 3 | 6-33442921-C-A | 69 | 4.28e-5 | -5.243 | Likely Benign | 0.276 | Likely Benign | Likely Benign | 0.103 | Likely Benign | -2.54 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | 2.27 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.1446 | 0.4653 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||
| c.2735C>A | T912N 2D AIThe SynGAP1 missense variant T912N is listed in ClinVar with an uncertain significance (ClinVar ID 2337624.0) and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. The SGM‑Consensus, 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. No Foldetta (FoldX‑MD/Rosetta) stability result 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 the current ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.740671 | Binding | 0.285 | 0.909 | 0.250 | Uncertain | 1 | -4.260 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.116 | Likely Benign | -1.15 | Neutral | 0.999 | Probably Damaging | 0.977 | Probably Damaging | 3.96 | Benign | 0.00 | Affected | 3.77 | 5 | 0.1095 | 0.3750 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||
| c.2924C>A | T975N 2D AIThe SynGAP1 missense variant T975N is listed in ClinVar (ID 942242.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443476‑C‑A). Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes. Only polyPhen‑2 HumDiv predicts a pathogenic effect. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: 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 preponderance of evidence points to a benign impact, 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 | 0.871313 | Disordered | 0.969331 | Binding | 0.332 | 0.890 | 0.625 | Uncertain | 1 | 6-33443476-C-A | 1 | 6.20e-7 | -4.671 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.58 | Neutral | 0.586 | Possibly Damaging | 0.302 | Benign | 4.13 | Benign | 0.07 | Tolerated | 4.32 | 2 | 0.1379 | 0.4772 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||
| c.3044C>A | T1015N 2D AIThe SynGAP1 missense variant T1015N 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 | 0.788093 | Disordered | 0.928486 | Binding | 0.295 | 0.823 | 0.625 | -4.353 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.027 | Likely Benign | 0.28 | Neutral | 0.004 | Benign | 0.002 | Benign | 2.54 | Benign | 0.24 | Tolerated | 0.1688 | 0.4233 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3053C>A | T1018N 2D AIThe SynGAP1 missense variant T1018N is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; the Foldetta protein‑folding stability analysis is unavailable for this variant. Overall, the majority of evidence points to a benign impact. The predictions do not contradict any ClinVar status, as no ClinVar claim exists for this variant. Thus, based on current computational predictions, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.849326 | Disordered | 0.959985 | Binding | 0.348 | 0.801 | 0.500 | -3.888 | Likely Benign | 0.165 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -1.74 | Neutral | 0.411 | Benign | 0.139 | Benign | 2.25 | Pathogenic | 0.01 | Affected | 0.1537 | 0.3979 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3113C>A | T1038N 2D AIThe SynGAP1 missense variant T1038N is not reported in ClinVar and has no entries in gnomAD, indicating it has not been catalogued in these databases. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the substitution as benign, while the majority‑vote consensus from SGM (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. Only polyPhen‑2 HumDiv predicts a pathogenic outcome, and AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates likely benign. No Foldetta stability analysis is available, so folding‑stability evidence is lacking. Overall, the preponderance of computational evidence supports a benign classification for T1038N, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this is not contradicted by ClinVar, which has no pathogenic designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.938133 | Disordered | 0.982911 | Binding | 0.279 | 0.794 | 0.625 | -3.837 | Likely Benign | 0.390 | Ambiguous | Likely Benign | 0.054 | Likely Benign | -1.36 | Neutral | 0.818 | Possibly Damaging | 0.355 | Benign | 2.68 | Benign | 0.10 | Tolerated | 0.1184 | 0.4490 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3401C>A | T1134N 2D AIThe SynGAP1 missense variant T1134N is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that T1134N 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 | 0.885302 | Disordered | 0.813034 | Binding | 0.335 | 0.885 | 0.875 | -4.368 | Likely Benign | 0.176 | Likely Benign | Likely Benign | 0.193 | Likely Benign | -0.34 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.42 | Benign | 0.04 | Affected | 0.1386 | 0.4870 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||||||||||||
| c.3689C>A | T1230N 2D AIThe SynGAP1 missense variant T1230N is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default all predict a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign likelihood. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign effect, 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 | -6.444 | Likely Benign | 0.613 | Likely Pathogenic | Likely Benign | 0.318 | Likely Benign | -2.15 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 5.50 | Benign | 0.02 | Affected | 0.0799 | 0.2870 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||||||||
| c.4019C>A | T1340N 2D AIThe SynGAP1 missense variant T1340N is reported in gnomAD (ID 6‑33451893‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for T1340N. 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 | 0.852992 | Disordered | 0.977899 | Binding | 0.444 | 0.697 | 0.750 | 6-33451893-C-A | -3.664 | Likely Benign | 0.154 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -0.95 | Neutral | 0.092 | Benign | 0.026 | Benign | 4.09 | Benign | 0.02 | Affected | 3.77 | 5 | 0.1755 | 0.5309 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||||||
| 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.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.881C>A | T294N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant T294N is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess functional impact uniformly classify the variant as pathogenic: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect. High‑accuracy methods reinforce this assessment: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts pathogenic. Based on the unanimous pathogenic predictions and the absence of any benign calls, the variant is most likely pathogenic, and this conclusion does not contradict the current ClinVar status (no report). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.328603 | Structured | 0.316932 | Uncertain | 0.919 | 0.267 | 0.125 | -14.925 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.74 | Destabilizing | 0.2 | 2.66 | Destabilizing | 2.70 | Destabilizing | 1.56 | Destabilizing | 0.630 | Likely Pathogenic | -4.60 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | -0.18 | Pathogenic | 0.01 | Affected | 0.1040 | 0.3239 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.884C>A | T295N 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 T295N missense variant is not reported in ClinVar (ClinVar ID None) and has no entries in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, ESM1b, and Foldetta, while those that predict a pathogenic outcome are SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, seven tools predict pathogenicity versus four predicting benign, with no ClinVar evidence to contradict this assessment. Thus, the variant is most likely pathogenic based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.401658 | Structured | 0.295548 | Uncertain | 0.881 | 0.288 | 0.125 | -6.588 | Likely Benign | 0.793 | Likely Pathogenic | Ambiguous | 0.24 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.45 | Likely Benign | 0.89 | Ambiguous | 0.438 | Likely Benign | -3.51 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 1.93 | Pathogenic | 0.03 | Affected | 0.1522 | 0.4457 | 0 | 0 | -2.8 | 13.00 | |||||||||||||||||||||||||||||
| c.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.95C>A | T32N 2D AIThe SynGAP1 missense variant T32N is catalogued in gnomAD (ID 6‑33423504‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. In contrast, polyPhen‑2 HumDiv and SIFT predict pathogenicity. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant, so its status is unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar classification (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.707965 | Disordered | 0.437154 | Uncertain | 0.349 | 0.879 | 0.375 | 6-33423504-C-A | 2 | 1.24e-6 | -3.466 | Likely Benign | 0.090 | Likely Benign | Likely Benign | 0.040 | Likely Benign | -1.01 | Neutral | 0.604 | Possibly Damaging | 0.140 | Benign | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1681 | 0.5264 | 0 | 0 | -2.8 | 13.00 | ||||||||||||||||||||||||||||||||||
| c.1014C>A | D338E 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -5.264 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.58 | Ambiguous | -0.01 | Likely Benign | 0.080 | Likely Benign | -1.95 | Neutral | 0.002 | Benign | 0.005 | Benign | 1.85 | Pathogenic | 0.55 | Tolerated | 0.1584 | 0.5397 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1014C>G | D338E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D338E is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicates a likely benign classification, while Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support from high‑accuracy methods, the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.335645 | Structured | 0.363354 | Uncertain | 0.460 | 0.438 | 0.375 | -5.264 | Likely Benign | 0.254 | Likely Benign | Likely Benign | 0.85 | Ambiguous | 0.3 | 0.31 | Likely Benign | 0.58 | Ambiguous | -0.01 | Likely Benign | 0.080 | Likely Benign | -1.95 | Neutral | 0.002 | Benign | 0.005 | Benign | 1.85 | Pathogenic | 0.55 | Tolerated | 0.1584 | 0.5397 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1022G>C | G341A 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant G341A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come only from polyPhen‑2 HumDiv and FATHMM. Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is likely benign; Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, remains inconclusive. Overall, the preponderance of evidence indicates that G341A 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 | 0.356642 | Structured | 0.431164 | Uncertain | 0.745 | 0.479 | 0.250 | -3.211 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.16 | Likely Benign | 0.4 | -1.23 | Ambiguous | -0.54 | Ambiguous | -0.03 | Likely Benign | 0.239 | Likely Benign | -1.13 | Neutral | 0.625 | Possibly Damaging | 0.192 | Benign | 0.43 | Pathogenic | 0.15 | Tolerated | 0.3562 | 0.3979 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1027G>A | V343I 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33437932‑G‑A). Prediction tools that uniformly indicate a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, resolves to “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments are consistent: AlphaMissense‑Optimized is benign; the SGM‑Consensus is likely benign; and Foldetta, combining FoldX‑MD and Rosetta outputs, is benign. Overall, the collective evidence strongly supports a benign classification, and this does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | Uncertain | 2 | 6-33437932-G-A | 1 | 6.20e-7 | -6.020 | Likely Benign | 0.117 | Likely Benign | Likely Benign | -0.27 | Likely Benign | 0.0 | -0.04 | Likely Benign | -0.16 | Likely Benign | -0.39 | Likely Benign | 0.020 | Likely Benign | -0.14 | Neutral | 0.159 | Benign | 0.084 | Benign | 1.98 | Pathogenic | 0.27 | Tolerated | 3.37 | 25 | 0.1095 | 0.4536 | 4 | 3 | 0.3 | 14.03 | 240.2 | -26.9 | -0.2 | 0.2 | -0.2 | 0.2 | X | Potentially Benign | The iso-propyl side chain of Val343, located in an anti-parallel β sheet strand (res. Gly341-Pro349), is packing against multiple hydrophobic residues of the C2 domain (e.g., Leu327, Leu274, Val365). In the variant simulations, the sec-butyl side chain of Ile343 is basically able to form the same interactions as valine due to its similar hydrophobic profile. The residue swap also does not seem to cause negative effects on the protein structure based on the simulations. | |||||||||||||
| c.1027G>C | V343L 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V343L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict benign or likely benign. Only FATHMM predicts a pathogenic outcome, while FoldX and Rosetta provide uncertain results and are therefore not considered decisive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. Overall, the majority of evidence supports a benign classification, and this is consistent with the absence of ClinVar reporting. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.291804 | Structured | 0.383911 | Uncertain | 0.882 | 0.497 | 0.250 | -6.268 | Likely Benign | 0.310 | Likely Benign | Likely Benign | -0.93 | Ambiguous | 0.2 | 0.66 | Ambiguous | -0.14 | Likely Benign | 0.16 | Likely Benign | 0.033 | Likely Benign | -1.09 | Neutral | 0.005 | Benign | 0.013 | Benign | 2.12 | Pathogenic | 0.64 | Tolerated | 0.1361 | 0.5008 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1031G>C | G344A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G344A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a deleterious effect: pathogenic predictions come from SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default, while only SIFT predicts a benign outcome. Two tools report uncertainty: premPS 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 consensus of the majority of predictors indicates 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 | C2 | 0.264545 | Structured | 0.368110 | Uncertain | 0.913 | 0.485 | 0.250 | -10.439 | Likely Pathogenic | 0.931 | Likely Pathogenic | Ambiguous | 5.11 | Destabilizing | 0.4 | 4.23 | Destabilizing | 4.67 | Destabilizing | 0.58 | Ambiguous | 0.873 | Likely Pathogenic | -5.38 | Deleterious | 1.000 | Probably Damaging | 0.999 | Probably Damaging | -0.32 | Pathogenic | 0.10 | Tolerated | 0.3964 | 0.5685 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1036G>C | V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results and are not used as evidence. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable predictors and the SGM‑Consensus support a pathogenic effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -8.178 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.05 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.58 | Ambiguous | 0.60 | Ambiguous | 0.384 | Likely Benign | -2.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.58 | Pathogenic | 0.09 | Tolerated | 0.1237 | 0.5348 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1036G>T | V346L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V346L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, and SIFT, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Default. Four tools (Foldetta, premPS, AlphaMissense‑Optimized, and Rosetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of evidence points toward a deleterious effect. Therefore, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.260850 | Structured | 0.350921 | Uncertain | 0.949 | 0.461 | 0.000 | -8.178 | Likely Pathogenic | 0.834 | Likely Pathogenic | Ambiguous | 0.05 | Likely Benign | 0.2 | 1.10 | Ambiguous | 0.58 | Ambiguous | 0.60 | Ambiguous | 0.386 | Likely Benign | -2.68 | Deleterious | 0.994 | Probably Damaging | 0.970 | Probably Damaging | 1.58 | Pathogenic | 0.09 | Tolerated | 0.1237 | 0.5348 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.103G>A | V35I 2D AIThe SynGAP1 missense variant V35I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (ID 6‑33423512‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome. No Foldetta stability data are available. Overall, the majority of evidence points to a benign impact, and this is consistent with the ClinVar “Uncertain” classification rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.613573 | Disordered | 0.434838 | Uncertain | 0.360 | 0.851 | 0.375 | Uncertain | 1 | 6-33423512-G-A | 5 | 3.10e-6 | -3.764 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.32 | Neutral | 0.672 | Possibly Damaging | 0.369 | Benign | 4.16 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0839 | 0.3757 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||
| c.103G>C | V35L 2D AIThe SynGAP1 missense variant V35L is reported in gnomAD (variant ID 6-33423512‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports it as likely benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT 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 majority of evidence, including the high‑accuracy tools, points to a benign effect. 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 Benign | 0.613573 | Disordered | 0.434838 | Uncertain | 0.360 | 0.851 | 0.375 | 6-33423512-G-C | 4 | 2.48e-6 | -2.893 | Likely Benign | 0.108 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.58 | Neutral | 0.481 | Possibly Damaging | 0.506 | Possibly Damaging | 4.18 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1026 | 0.4025 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.1042G>C | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | 0.072 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 0.1088 | 0.4953 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1042G>T | V348L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V348L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No other high‑confidence tools provide conflicting evidence. Based on the preponderance of predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.170161 | Structured | 0.346556 | Uncertain | 0.951 | 0.414 | 0.000 | -4.842 | Likely Benign | 0.270 | Likely Benign | Likely Benign | -0.58 | Ambiguous | 0.0 | 0.04 | Likely Benign | -0.27 | Likely Benign | 0.24 | Likely Benign | 0.072 | Likely Benign | -0.75 | Neutral | 0.264 | Benign | 0.030 | Benign | 1.89 | Pathogenic | 0.62 | Tolerated | 0.1088 | 0.4953 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1048G>C | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as uncertain. No other tools provide conflicting evidence. Based on the preponderance of benign predictions and the lack of pathogenic support, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | 0.042 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 0.1173 | 0.4958 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1048G>T | V350L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V350L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only FATHMM predicts a pathogenic outcome, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign status. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. No other tools provide conflicting evidence. Based on the preponderance of predictions, V350L is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.179055 | Structured | 0.353227 | Uncertain | 0.931 | 0.371 | 0.000 | -5.941 | Likely Benign | 0.238 | Likely Benign | Likely Benign | -1.31 | Ambiguous | 0.1 | -0.34 | Likely Benign | -0.83 | Ambiguous | 0.36 | Likely Benign | 0.042 | Likely Benign | -1.63 | Neutral | 0.068 | Benign | 0.022 | Benign | 2.37 | Pathogenic | 0.27 | Tolerated | 0.1173 | 0.4958 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1064G>C | G355A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G355A 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. FoldX and Foldetta are uncertain and therefore not counted as evidence. 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 uncertain. Consequently, the overall prediction leans toward a benign effect, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.155435 | Structured | 0.388832 | Uncertain | 0.810 | 0.354 | 0.125 | -5.431 | Likely Benign | 0.245 | Likely Benign | Likely Benign | 0.88 | Ambiguous | 0.6 | 0.46 | Likely Benign | 0.67 | Ambiguous | 0.49 | Likely Benign | 0.286 | Likely Benign | -4.80 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.80 | Pathogenic | 0.03 | Affected | 0.4111 | 0.5045 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.1093G>A | V365I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6‑33437998‑G‑A). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | Uncertain | 1 | 6-33437998-G-A | 4 | 2.65e-6 | -5.943 | Likely Benign | 0.155 | Likely Benign | Likely Benign | -0.65 | Ambiguous | 0.2 | -0.11 | Likely Benign | -0.38 | Likely Benign | 0.13 | Likely Benign | 0.036 | Likely Benign | -0.47 | Neutral | 0.451 | Benign | 0.137 | Benign | 1.76 | Pathogenic | 0.10 | Tolerated | 3.38 | 21 | 0.0657 | 0.4447 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||
| c.1093G>C | V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact uniformly classify the substitution as benign: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity; only FoldX and Rosetta report uncertain stability changes, which are treated as unavailable evidence. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, reports a benign effect on protein folding stability. Based on the collective predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | -6.141 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | 0.065 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 0.0852 | 0.5309 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||
| c.1093G>T | V365L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V365L is catalogued in gnomAD (ID 6‑33437998‑G‑T) but has no ClinVar entry. Across the available in‑silico predictors, the majority (REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv/HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly classify the change as benign; only FoldX and Rosetta report uncertain stability effects, which are treated as unavailable evidence. High‑accuracy assessments reinforce this benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (derived from the unanimous benign vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts a benign impact. Consequently, the variant is most likely benign based on current computational evidence, 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 | C2 | 0.414856 | Structured | 0.441505 | Uncertain | 0.923 | 0.608 | 0.250 | 6-33437998-G-T | 5 | 3.31e-6 | -6.141 | Likely Benign | 0.265 | Likely Benign | Likely Benign | -0.72 | Ambiguous | 0.2 | 0.74 | Ambiguous | 0.01 | Likely Benign | 0.35 | Likely Benign | 0.065 | Likely Benign | -1.71 | Neutral | 0.005 | Benign | 0.003 | Benign | 2.50 | Benign | 0.25 | Tolerated | 3.38 | 21 | 0.0852 | 0.5309 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||
| c.109T>A | S37T 2D  AIThe SynGAP1 missense variant S37T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign 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 | 0.642678 | Disordered | 0.433492 | Uncertain | 0.317 | 0.806 | 0.500 | -3.854 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.60 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 3.95 | Benign | 0.00 | Affected | 0.2093 | 0.5974 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.10T>A | S4T 2D AIThe SynGAP1 missense variant S4T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, all of which are benign, and therefore SGM‑Consensus also predicts benign. AlphaMissense‑Optimized independently predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy tools indicates that 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 | 0.608892 | Disordered | 0.547364 | Binding | 0.390 | 0.924 | 0.750 | -4.598 | Likely Benign | 0.130 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -0.01 | Neutral | 0.140 | Benign | 0.153 | Benign | 4.18 | Benign | 0.00 | Affected | 0.1383 | 0.6572 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1109G>C | G370A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G370A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Pathogenic predictions come from FoldX, Foldetta, and FATHMM, while Rosetta remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also indicating a likely benign outcome, and Foldetta suggesting a pathogenic impact via combined FoldX‑MD and Rosetta stability analysis. Overall, the majority of evidence points to a benign effect, with only a minority of tools predicting pathogenicity. There is no ClinVar entry to contradict this assessment, so 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 | C2 | 0.461924 | Structured | 0.434325 | Uncertain | 0.359 | 0.720 | 0.500 | -3.334 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 1.3 | 1.62 | Ambiguous | 2.03 | Destabilizing | -0.14 | Likely Benign | 0.304 | Likely Benign | 0.54 | Neutral | 0.000 | Benign | 0.000 | Benign | 1.33 | Pathogenic | 0.79 | Tolerated | 0.3883 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1112G>C | S371T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S371T 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 reports 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 | 0.444081 | Structured | 0.432086 | Uncertain | 0.294 | 0.746 | 0.375 | -4.512 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.38 | Likely Benign | 0.1 | -0.27 | Likely Benign | 0.06 | Likely Benign | 0.05 | Likely Benign | 0.173 | Likely Benign | -0.65 | Neutral | 0.213 | Benign | 0.067 | Benign | 4.64 | Benign | 0.22 | Tolerated | 0.2245 | 0.6462 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1115G>C | G372A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G372A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. FoldX and Rosetta individually also return uncertain results. Overall, the majority of evidence points to a benign impact for G372A, and this conclusion does not contradict any ClinVar status, as the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.433034 | Structured | 0.430335 | Uncertain | 0.322 | 0.774 | 0.375 | -5.163 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 1.52 | Ambiguous | 0.2 | 1.58 | Ambiguous | 1.55 | Ambiguous | -0.12 | Likely Benign | 0.465 | Likely Benign | -0.32 | Neutral | 0.000 | Benign | 0.000 | Benign | -0.74 | Pathogenic | 0.03 | Affected | 0.3956 | 0.5247 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1118G>C | G373A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G373A is not reported in ClinVar and is absent from gnomAD. Functional prediction consensus shows a predominance of benign calls: REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all predict a benign effect. Pathogenic predictions are limited to SIFT and FoldX, while Rosetta and Foldetta yield uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta remains inconclusive. Overall, the majority of evidence indicates that G373A is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.529623 | Disordered | 0.429267 | Uncertain | 0.295 | 0.799 | 0.625 | -5.181 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 2.44 | Destabilizing | 0.8 | 0.69 | Ambiguous | 1.57 | Ambiguous | -0.01 | Likely Benign | 0.227 | Likely Benign | -0.47 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.93 | Benign | 0.01 | Affected | 0.4172 | 0.5053 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1120T>A | S374T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S374T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts pathogenicity. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is uncertain but does not indicate destabilization. Overall, the evidence strongly favors a benign effect for S374T, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.642678 | Disordered | 0.428948 | Uncertain | 0.333 | 0.812 | 0.625 | -5.415 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.39 | Likely Benign | 0.1 | 0.80 | Ambiguous | 0.60 | Ambiguous | -0.02 | Likely Benign | 0.176 | Likely Benign | -0.47 | Neutral | 0.118 | Benign | 0.049 | Benign | 5.32 | Benign | 0.12 | Tolerated | 0.2212 | 0.6466 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1124G>C | G375A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G375A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is labeled “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of evidence points to a benign effect; this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.604312 | Disordered | 0.428340 | Uncertain | 0.301 | 0.836 | 0.625 | -5.986 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 2.52 | Destabilizing | 1.0 | 3.16 | Destabilizing | 2.84 | Destabilizing | -0.09 | Likely Benign | 0.419 | Likely Benign | -0.61 | Neutral | 0.020 | Benign | 0.008 | Benign | 1.33 | Pathogenic | 0.27 | Tolerated | 0.3991 | 0.5242 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1127G>C | G376A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G376A missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, PROVEAN, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. FoldX and Rosetta give uncertain results and are not considered evidence for either side. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates benign; and Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, predicts benign. Overall, the majority of evidence points to a benign impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.680603 | Disordered | 0.428979 | Uncertain | 0.326 | 0.869 | 0.625 | -6.016 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 1.74 | Ambiguous | 0.3 | -0.84 | Ambiguous | 0.45 | Likely Benign | 0.00 | Likely Benign | 0.392 | Likely Benign | -0.44 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 1.33 | Pathogenic | 0.03 | Affected | 0.3868 | 0.4465 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1133G>C | G378A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G378A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as “Likely Benign.” High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, SGM‑Consensus confirms a benign likelihood, while Foldetta—combining FoldX‑MD and Rosetta outputs—predicts a pathogenic effect on protein folding stability. Overall, the majority of evidence points toward a benign impact, and this conclusion is consistent with the absence of ClinVar annotation and gnomAD data. Thus, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.767246 | Disordered | 0.432858 | Uncertain | 0.341 | 0.915 | 0.625 | -6.450 | Likely Benign | 0.111 | Likely Benign | Likely Benign | 5.06 | Destabilizing | 1.3 | 6.00 | Destabilizing | 5.53 | Destabilizing | -0.04 | Likely Benign | 0.497 | Likely Benign | -0.55 | Neutral | 0.999 | Probably Damaging | 0.981 | Probably Damaging | 1.33 | Pathogenic | 0.18 | Tolerated | 0.4062 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1135T>A | S379T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S379T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are Rosetta, polyPhen‑2 HumDiv, and the Foldetta stability method. FoldX is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as pathogenic. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.433206 | Uncertain | 0.327 | 0.931 | 0.625 | -5.646 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 1.42 | Ambiguous | 0.6 | 3.96 | Destabilizing | 2.69 | Destabilizing | 0.06 | Likely Benign | 0.230 | Likely Benign | -0.50 | Neutral | 0.462 | Possibly Damaging | 0.084 | Benign | 3.87 | Benign | 0.16 | Tolerated | 0.2293 | 0.6248 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1139G>C | G380A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G380A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FoldX predicts a pathogenic outcome, while Rosetta and Foldetta are benign or uncertain, respectively. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as benign, and Foldetta as uncertain. Overall, the overwhelming majority of evidence points to a benign effect, with no conflict with ClinVar status (which has no entry for this variant). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.724957 | Disordered | 0.432982 | Uncertain | 0.316 | 0.939 | 0.750 | -6.433 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 3.11 | Destabilizing | 1.0 | -0.15 | Likely Benign | 1.48 | Ambiguous | -0.06 | Likely Benign | 0.422 | Likely Benign | -0.53 | Neutral | 0.056 | Benign | 0.010 | Benign | 2.56 | Benign | 0.17 | Tolerated | 0.3915 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1142G>C | G381A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G381A is reported in gnomAD (variant ID 6-33438047‑G‑C) but has no ClinVar entry. Functional prediction tools fall into two groups: benign predictions come from premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and polyPhen‑2 HumVar; pathogenic predictions come from REVEL, FoldX, Rosetta, polyPhen‑2 HumDiv, FATHMM, and the SGM‑Consensus score. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely benign, while Foldetta (combining FoldX‑MD and Rosetta stability outputs) indicates a pathogenic effect. No prediction or stability result is missing or inconclusive. Overall, the majority of tools suggest a benign effect, and the high‑accuracy consensus leans toward benign, though Foldetta’s pathogenic signal introduces uncertainty. The variant is most likely benign based on the collective predictions, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.724957 | Disordered | 0.431692 | Uncertain | 0.301 | 0.951 | 0.750 | 6-33438047-G-C | 1 | 6.23e-7 | -6.266 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 3.97 | Destabilizing | 0.7 | 2.05 | Destabilizing | 3.01 | Destabilizing | 0.06 | Likely Benign | 0.507 | Likely Pathogenic | -0.63 | Neutral | 0.718 | Possibly Damaging | 0.332 | Benign | 1.33 | Pathogenic | 0.52 | Tolerated | 4.32 | 9 | 0.3809 | 0.4770 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||
| c.1145G>C | G382A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G382A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a pathogenic impact. Overall, the majority of predictions lean toward a benign effect, and this consensus does not contradict any ClinVar status (none available). Thus, based on the available computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.728858 | Disordered | 0.429690 | Uncertain | 0.315 | 0.951 | 0.750 | -6.323 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 2.90 | Destabilizing | 0.6 | 3.00 | Destabilizing | 2.95 | Destabilizing | -0.03 | Likely Benign | 0.495 | Likely Benign | -0.59 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.12 | Tolerated | 0.4048 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1148G>C | G383A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G383A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, Rosetta, and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as pathogenic. Thus, the majority of evidence points to a benign impact, with only a minority of high‑accuracy tools suggesting pathogenicity. The variant is most likely benign based on the overall predictions, 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 | C2 | 0.728858 | Disordered | 0.429104 | Uncertain | 0.296 | 0.949 | 0.750 | -6.205 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 3.17 | Destabilizing | 1.2 | 3.47 | Destabilizing | 3.32 | Destabilizing | 0.04 | Likely Benign | 0.178 | Likely Benign | -0.64 | Neutral | 0.055 | Benign | 0.037 | Benign | 4.20 | Benign | 0.11 | Tolerated | 0.3880 | 0.4361 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1151G>C | G384A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G384A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that classify the variant as benign include REVEL, premPS, PROVEAN, 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, SIFT, FATHMM, and Rosetta. Predictions from FoldX and Foldetta are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation. 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 | C2 | 0.728858 | Disordered | 0.427831 | Uncertain | 0.323 | 0.934 | 0.750 | -6.927 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 1.81 | Ambiguous | 0.2 | 2.16 | Destabilizing | 1.99 | Ambiguous | 0.04 | Likely Benign | 0.307 | Likely Benign | -0.40 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.05 | Affected | 0.3986 | 0.4576 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1153T>A | S385T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S385T is not 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, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only polyPhen‑2 HumVar and SIFT 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—AlphaMissense‑Optimized, the SGM‑Consensus, and Foldetta (combining FoldX‑MD and Rosetta outputs)—all indicate a benign effect. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.425480 | Uncertain | 0.341 | 0.925 | 0.750 | -5.904 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.65 | Ambiguous | 0.2 | 0.05 | Likely Benign | 0.35 | Likely Benign | -0.12 | Likely Benign | 0.214 | Likely Benign | -0.31 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 4.64 | Benign | 0.03 | Affected | 0.2266 | 0.6259 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1157G>C | G386A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change G386A has no ClinVar entry and is not reported in gnomAD. Consensus predictions from multiple in‑silico tools cluster into two groups: benign (SGM‑Consensus, REVEL, premPS, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, polyPhen‑2 HumVar) and pathogenic (FoldX, polyPhen‑2 HumDiv, SIFT). Two tools report uncertainty: Rosetta and Foldetta. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, while Foldetta’s stability analysis is inconclusive. Overall, the majority of evidence points to a benign effect for G386A. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.733139 | Disordered | 0.424156 | Uncertain | 0.334 | 0.898 | 0.750 | -6.453 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 2.14 | Destabilizing | 0.7 | 1.05 | Ambiguous | 1.60 | Ambiguous | 0.14 | Likely Benign | 0.331 | Likely Benign | -0.55 | Neutral | 0.718 | Possibly Damaging | 0.332 | Benign | 3.93 | Benign | 0.05 | Affected | 0.3815 | 0.4868 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1160G>C | G387A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G387A is reported in gnomAD (variant ID 6‑33438065‑G‑C) but has no ClinVar entry. 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 change as benign. Only FATHMM predicts it as pathogenic. 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, which integrates FoldX‑MD and Rosetta stability outputs, is inconclusive (treated as unavailable). No other tools provide decisive evidence. 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 | C2 | 0.642678 | Disordered | 0.422910 | Uncertain | 0.293 | 0.861 | 0.750 | 6-33438065-G-C | 3 | 1.87e-6 | -6.313 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 1.95 | Ambiguous | 0.1 | 1.68 | Ambiguous | 1.82 | Ambiguous | -0.02 | Likely Benign | 0.300 | Likely Benign | -0.29 | Neutral | 0.007 | Benign | 0.010 | Benign | 1.33 | Pathogenic | 0.06 | Tolerated | 4.32 | 3 | 0.4149 | 0.4576 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||
| c.1163G>C | G388A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G388A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, SGM‑Consensus as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as Pathogenic. Overall, the predictions are mixed, but the two most reliable tools (AlphaMissense‑Optimized and SGM‑Consensus) favor a benign interpretation, while Foldetta suggests instability. Based on the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.736850 | Disordered | 0.420316 | Uncertain | 0.319 | 0.827 | 0.750 | -6.577 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 2.55 | Destabilizing | 1.9 | 3.57 | Destabilizing | 3.06 | Destabilizing | -0.04 | Likely Benign | 0.457 | Likely Benign | -0.57 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 1.33 | Pathogenic | 0.05 | Affected | 0.3969 | 0.4837 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1165T>A | S389T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S389T is not reported in ClinVar and is present in gnomAD (variant ID 6‑33438070‑T‑A). Functional prediction tools that converge on a benign outcome include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 HumVar and SIFT predict a pathogenic effect. 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, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign outcome. Taken together, the majority of evidence supports a benign classification for S389T, and this conclusion is consistent with the absence of a ClinVar pathogenic report. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.703578 | Disordered | 0.417444 | Uncertain | 0.306 | 0.803 | 0.875 | 6-33438070-T-A | -5.403 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.2 | 0.11 | Likely Benign | 0.24 | Likely Benign | -0.04 | Likely Benign | 0.242 | Likely Benign | -0.26 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 5.07 | Benign | 0.03 | Affected | 4.32 | 8 | 0.2317 | 0.6656 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||
| c.1169G>C | G390A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G390A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, FATHMM, and Rosetta. The high‑accuracy assessment shows AlphaMissense‑Optimized as benign, the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely benign, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as pathogenic. FoldX alone is inconclusive. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.626927 | Disordered | 0.413274 | Uncertain | 0.304 | 0.763 | 0.875 | -6.768 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 1.96 | Ambiguous | 0.4 | 2.03 | Destabilizing | 2.00 | Destabilizing | 0.02 | Likely Benign | 0.402 | Likely Benign | -0.55 | Neutral | 0.143 | Benign | 0.028 | Benign | 1.33 | Pathogenic | 0.05 | Affected | 0.4130 | 0.5053 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1172G>C | G391A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G391A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are FoldX, polyPhen‑2 HumDiv, and FATHMM. Predictions that are inconclusive are Rosetta and Foldetta. The high‑accuracy consensus from AlphaMissense‑Optimized is benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is also likely benign, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign effect, and this is consistent with the lack of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.637480 | Disordered | 0.409509 | Uncertain | 0.279 | 0.741 | 0.750 | -5.712 | Likely Benign | 0.120 | Likely Benign | Likely Benign | 2.02 | Destabilizing | 0.5 | 1.92 | Ambiguous | 1.97 | Ambiguous | 0.11 | Likely Benign | 0.442 | Likely Benign | -0.76 | Neutral | 0.633 | Possibly Damaging | 0.219 | Benign | 1.33 | Pathogenic | 0.19 | Tolerated | 0.3828 | 0.4870 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1178G>C | G393A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G393A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Only FATHMM predicts a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta) are inconclusive, so they provide no evidence for or against pathogenicity. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign effect, and there is no ClinVar annotation to contradict this assessment. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.538167 | Disordered | 0.402365 | Uncertain | 0.333 | 0.670 | 0.625 | -4.507 | Likely Benign | 0.129 | Likely Benign | Likely Benign | 1.93 | Ambiguous | 0.5 | -0.68 | Ambiguous | 0.63 | Ambiguous | 0.22 | Likely Benign | 0.381 | Likely Benign | -1.89 | Neutral | 0.176 | Benign | 0.039 | Benign | 1.33 | Pathogenic | 0.08 | Tolerated | 0.4143 | 0.5193 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1184G>C | G395A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G395A is not 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive results come from FoldX and Rosetta, which are treated as unavailable. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.513880 | Disordered | 0.396199 | Uncertain | 0.474 | 0.601 | 0.500 | -3.964 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 1.51 | Ambiguous | 0.3 | -0.59 | Ambiguous | 0.46 | Likely Benign | 0.08 | Likely Benign | 0.160 | Likely Benign | -0.72 | Neutral | 0.001 | Benign | 0.003 | Benign | 4.24 | Benign | 0.15 | Tolerated | 0.3848 | 0.5047 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1187G>C | G396A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G396A 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 predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also yields a benign verdict, while Foldetta (combining FoldX‑MD and Rosetta outputs) is inconclusive. Consequently, the variant is most likely benign based on the available predictions, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.414856 | Structured | 0.394626 | Uncertain | 0.640 | 0.584 | 0.500 | -3.655 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 1.74 | Ambiguous | 0.7 | 1.90 | Ambiguous | 1.82 | Ambiguous | 0.41 | Likely Benign | 0.274 | Likely Benign | -1.28 | Neutral | 0.062 | Benign | 0.024 | Benign | 3.93 | Benign | 0.84 | Tolerated | 0.3846 | 0.5255 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1198G>C | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is listed in ClinVar as Benign (ClinVar ID 1166313) and is present in gnomAD (6‑33438103‑G‑C). Prediction tools that agree on a benign effect include REVEL, FoldX‑MD (uncertain), Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; no tool predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts 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 predictions, the variant is most likely benign, and this conclusion is consistent with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | Benign/Likely benign | 2 | 6-33438103-G-C | 22 | 1.36e-5 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | 0.325 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 0.1006 | 0.5242 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||
| c.1198G>T | V400L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V400L is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Functional prediction tools that agree on a benign effect include REVEL, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, premPS, AlphaMissense‑Default, AlphaMissense‑Optimized, and Rosetta. No tool predicts a pathogenic outcome; the only inconclusive result is from FoldX (Uncertain). High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts Benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields Likely Benign; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Benign. Based on the collective evidence, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.398279 | Structured | 0.415488 | Uncertain | 0.951 | 0.451 | 0.000 | -1.000 | Likely Benign | 0.137 | Likely Benign | Likely Benign | -0.71 | Ambiguous | 0.2 | 0.39 | Likely Benign | -0.16 | Likely Benign | -0.29 | Likely Benign | 0.325 | Likely Benign | -0.60 | Neutral | 0.001 | Benign | 0.001 | Benign | 5.33 | Benign | 0.64 | Tolerated | 3.38 | 27 | 0.1006 | 0.5242 | 2 | 1 | -0.4 | 14.03 | 251.0 | -30.1 | 0.0 | 0.0 | 0.7 | 0.1 | X | Potentially Benign | The iso-propyl side chain of Val400, located in an anti-parallel β sheet strand (res. Ala399-Ile411), hydrophobically packs against hydrophobic residues within the anti-parallel β sheet of the C2 domain (e.g., Ile268, Ala404, Leu325, Leu402). Val400 is swapped for another hydrophobic residue, leucine, whose branched hydrocarbon side chain is of a comparable size and thus packs favorably within the C2 domain. In short, the residue swap has no apparent negative effect on the structure based on the variant simulations. | 10.1016/j.ajhg.2020.11.011 | |||||||||||||||||
| c.120T>A | D40E 2D AIThe SynGAP1 missense variant D40E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, 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 | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -3.520 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.21 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.00 | Affected | 0.2764 | 0.8141 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.120T>G | D40E 2D AIThe SynGAP1 missense variant D40E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign consensus. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Thus, the variant is most likely benign, and this assessment does not contradict the ClinVar record, which contains no pathogenic claim. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.384043 | Structured | 0.432002 | Uncertain | 0.319 | 0.769 | 0.375 | -3.520 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.050 | Likely Benign | -0.21 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.20 | Benign | 0.00 | Affected | 0.2764 | 0.8141 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1229G>C | S410T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S410T has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, PROVEAN, FoldX, Foldetta, SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, and premPS. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. **Thus, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.098513 | Structured | 0.349627 | Uncertain | 0.908 | 0.206 | 0.000 | -6.559 | Likely Benign | 0.123 | Likely Benign | Likely Benign | -0.32 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.42 | Likely Benign | 0.00 | Likely Benign | 0.066 | Likely Benign | -0.78 | Neutral | 0.080 | Benign | 0.026 | Benign | 4.24 | Benign | 0.84 | Tolerated | 0.1371 | 0.7159 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1270G>A | V424I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V424I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the substitution as tolerated or benign. The only inconclusive results come from FoldX (uncertain) and Foldetta (uncertain). When high‑accuracy methods are considered separately, AlphaMissense‑Optimized predicts benign, the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also predicts benign, while Foldetta remains uncertain. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar annotation (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -3.814 | Likely Benign | 0.095 | Likely Benign | Likely Benign | -1.04 | Ambiguous | 0.1 | -0.48 | Likely Benign | -0.76 | Ambiguous | 0.02 | Likely Benign | 0.084 | Likely Benign | -0.15 | Neutral | 0.013 | Benign | 0.006 | Benign | 3.50 | Benign | 0.63 | Tolerated | 0.0874 | 0.2609 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.1270G>C | V424L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V424L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome, while SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) reports a likely benign classification. Stability‑based methods are inconclusive: FoldX is uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) is also uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar status because no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.050641 | Structured | 0.411431 | Uncertain | 0.973 | 0.248 | 0.000 | -4.941 | Likely Benign | 0.742 | Likely Pathogenic | Likely Benign | -0.90 | Ambiguous | 0.2 | -0.41 | Likely Benign | -0.66 | Ambiguous | 0.43 | Likely Benign | 0.159 | Likely Benign | -1.68 | Neutral | 0.327 | Benign | 0.026 | Benign | 4.50 | Benign | 0.59 | Tolerated | 0.1018 | 0.2680 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.128G>C | G43A 2D AIThe SynGAP1 missense variant G43A is reported in gnomAD (variant ID 6-33423537‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts it to be pathogenic, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus itself is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign effect for G43A, 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 | 0.308712 | Structured | 0.431462 | Uncertain | 0.396 | 0.762 | 0.375 | 6-33423537-G-C | 2 | 1.24e-6 | -3.925 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.005 | Benign | 4.29 | Benign | 0.00 | Affected | 4.32 | 1 | 0.3677 | 0.3450 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.1300G>A | V434I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434I (ClinVar ID 212346.0, status Uncertain) is present in gnomAD (ID 6‑33438205‑G‑A). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. No predictions or stability results are missing or inconclusive. Based on the collective evidence, the variant is most likely benign, which does not contradict the ClinVar status of Uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | Uncertain | 1 | 6-33438205-G-A | 1 | 6.19e-7 | -6.999 | Likely Benign | 0.129 | Likely Benign | Likely Benign | -0.04 | Likely Benign | 0.0 | 0.22 | Likely Benign | 0.09 | Likely Benign | 0.31 | Likely Benign | 0.192 | Likely Benign | -0.82 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.53 | Benign | 0.18 | Tolerated | 3.37 | 29 | 0.0675 | 0.3415 | 4 | 3 | 0.3 | 14.03 | 246.7 | -27.7 | 0.0 | 0.0 | 0.1 | 0.0 | X | Potentially Benign | The iso-propyl side chain of Val434, located at the end of an α helix (res. Met414-Glu436), packs against hydrophobic residues in an interhelix space (e.g., Met430, Ala707, Leu711). In the variant simulations, the sec-butyl group of Ile434 is able to form the same hydrophobic interactions. Accordingly, the residue swap does not negatively affect the protein structure based on the simulations. | |||||||||||||
| c.1300G>C | V434L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V434L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, SIFT, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Two tools, Rosetta and AlphaMissense‑Default, give uncertain results. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, a protein‑folding stability method, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that V434L is most likely benign, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.158265 | Structured | 0.342846 | Uncertain | 0.954 | 0.306 | 0.000 | -8.697 | Likely Pathogenic | 0.477 | Ambiguous | Likely Benign | -0.05 | Likely Benign | 0.0 | 1.02 | Ambiguous | 0.49 | Likely Benign | 0.20 | Likely Benign | 0.225 | Likely Benign | -2.30 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.64 | Benign | 0.27 | Tolerated | 0.0895 | 0.3813 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1321G>A | V441I 2D AIThe SynGAP1 missense variant V441I is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only ESM1b predicts it as pathogenic. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. No contradictory evidence is present. Based on the collective predictions, the variant is most likely benign, and this conclusion does not conflict with the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -8.773 | Likely Pathogenic | 0.122 | Likely Benign | Likely Benign | -0.24 | Likely Benign | 0.3 | 0.11 | Likely Benign | -0.07 | Likely Benign | 0.25 | Likely Benign | 0.135 | Likely Benign | -0.82 | Neutral | 0.287 | Benign | 0.038 | Benign | 3.41 | Benign | 0.16 | Tolerated | 0.0694 | 0.3412 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.1321G>C | V441L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V441L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the preponderance of evidence, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.161087 | Structured | 0.259875 | Uncertain | 0.918 | 0.249 | 0.000 | -9.546 | Likely Pathogenic | 0.395 | Ambiguous | Likely Benign | -0.43 | Likely Benign | 0.0 | 0.59 | Ambiguous | 0.08 | Likely Benign | 0.45 | Likely Benign | 0.135 | Likely Benign | -2.27 | Neutral | 0.165 | Benign | 0.028 | Benign | 3.43 | Benign | 0.11 | Tolerated | 0.0961 | 0.3881 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1328G>C | G443A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G443A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that reach a consensus all indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the substitution as tolerated. No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the variant as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. The protein‑folding stability predictor Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result and is therefore treated as unavailable evidence. Overall, the collective predictions strongly suggest that the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.258623 | Uncertain | 0.935 | 0.206 | 0.000 | -0.332 | Likely Benign | 0.101 | Likely Benign | Likely Benign | -0.59 | Ambiguous | 0.1 | -1.61 | Ambiguous | -1.10 | Ambiguous | -0.52 | Ambiguous | 0.033 | Likely Benign | -1.04 | Neutral | 0.022 | Benign | 0.011 | Benign | 3.41 | Benign | 0.54 | Tolerated | 0.3539 | 0.3192 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1339G>A | V447I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate a benign or likely benign outcome. Only two tools, polyPhen‑2 HumDiv and HumVar, predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely benign, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign stability. Thus, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | -5.067 | Likely Benign | 0.167 | Likely Benign | Likely Benign | -0.33 | Likely Benign | 0.1 | 0.27 | Likely Benign | -0.03 | Likely Benign | -0.44 | Likely Benign | 0.117 | Likely Benign | -0.06 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.37 | Benign | 0.28 | Tolerated | 0.0625 | 0.3059 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.1339G>C | V447L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V447L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict pathogenicity are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. Uncertain results are reported by FoldX, Rosetta, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Overall, the majority of evidence points to a benign effect, and this consensus does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.250310 | Structured | 0.283801 | Uncertain | 0.970 | 0.243 | 0.000 | Uncertain | 1 | -5.136 | Likely Benign | 0.491 | Ambiguous | Likely Benign | -1.13 | Ambiguous | 0.1 | 0.54 | Ambiguous | -0.30 | Likely Benign | 0.03 | Likely Benign | 0.180 | Likely Benign | -0.29 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.61 | Benign | 0.90 | Tolerated | 3.37 | 32 | 0.0757 | 0.3477 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1346G>C | S449T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S449T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify it as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments are consistent: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus predicts likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on these predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status (which has no entry). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.254060 | Structured | 0.301437 | Uncertain | 0.958 | 0.251 | 0.000 | -6.262 | Likely Benign | 0.115 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.1 | -0.46 | Likely Benign | -0.05 | Likely Benign | -0.15 | Likely Benign | 0.039 | Likely Benign | -1.48 | Neutral | 0.038 | Benign | 0.008 | Benign | 3.42 | Benign | 0.33 | Tolerated | 0.1219 | 0.5077 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1354G>A | V452I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V452I variant is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Rosetta 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) resolves to benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts benign. 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. | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | Uncertain | 2 | -8.985 | Likely Pathogenic | 0.361 | Ambiguous | Likely Benign | -0.08 | Likely Benign | 0.1 | 0.51 | Ambiguous | 0.22 | Likely Benign | 0.25 | Likely Benign | 0.218 | Likely Benign | -0.99 | Neutral | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.26 | Benign | 0.05 | Affected | 0.0630 | 0.3476 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||
| c.1354G>C | V452L 2D 3DClick to see structure in 3D Viewer AISynGAP1 V452L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Because the majority of tools (six) predict benign and the high‑accuracy Foldetta also supports benign, the variant is most likely benign, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.335645 | Structured | 0.315167 | Uncertain | 0.970 | 0.229 | 0.000 | -11.285 | Likely Pathogenic | 0.929 | Likely Pathogenic | Ambiguous | 0.29 | Likely Benign | 0.1 | -0.25 | Likely Benign | 0.02 | Likely Benign | 0.34 | Likely Benign | 0.316 | Likely Benign | -2.96 | Deleterious | 0.947 | Possibly Damaging | 0.851 | Possibly Damaging | 3.54 | Benign | 0.11 | Tolerated | 0.0777 | 0.4061 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1370G>C | S457T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S457T has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, Foldetta, premPS, SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. FoldX and Rosetta provide uncertain results and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) predicting likely pathogenic, and Foldetta predicting benign. Overall, the majority of high‑confidence tools lean toward a benign effect, and there is no conflict with the ClinVar status, which is currently unreported. Thus, the variant is most likely benign based on the available predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.164327 | Structured | 0.297330 | Uncertain | 0.909 | 0.159 | 0.000 | -8.772 | Likely Pathogenic | 0.723 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.1 | -0.57 | Ambiguous | 0.13 | Likely Benign | 0.38 | Likely Benign | 0.273 | Likely Benign | -2.83 | Deleterious | 0.866 | Possibly Damaging | 0.780 | Possibly Damaging | 3.34 | Benign | 0.09 | Tolerated | 0.1154 | 0.6487 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1376G>C | G459A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G459A missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools cluster into two consensus groups: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Predictions labeled Uncertain (Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, is Uncertain and therefore not considered evidence. Overall, the majority of reliable tools indicate a pathogenic impact, and this conclusion does not contradict any ClinVar annotation (none present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.185198 | Structured | 0.289888 | Uncertain | 0.903 | 0.150 | 0.125 | -11.684 | Likely Pathogenic | 0.961 | Likely Pathogenic | Likely Pathogenic | 2.44 | Destabilizing | 0.1 | 0.90 | Ambiguous | 1.67 | Ambiguous | 0.72 | Ambiguous | 0.469 | Likely Benign | -5.63 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.06 | Benign | 0.01 | Affected | 0.3529 | 0.5161 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1389C>A | D463E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and premPS. Only PROVEAN predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -5.170 | Likely Benign | 0.527 | Ambiguous | Likely Benign | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | 0.162 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 0.1330 | 0.5177 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1389C>G | D463E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D463E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and premPS. Only PROVEAN predicts a pathogenic outcome, while Rosetta and AlphaMissense‑Default are uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) resolves to benign, and Foldetta also indicates benign stability. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the collective evidence, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.260850 | Structured | 0.305622 | Uncertain | 0.940 | 0.176 | 0.000 | -5.170 | Likely Benign | 0.527 | Ambiguous | Likely Benign | -0.42 | Likely Benign | 0.1 | 0.50 | Ambiguous | 0.04 | Likely Benign | 0.47 | Likely Benign | 0.162 | Likely Benign | -2.58 | Deleterious | 0.012 | Benign | 0.003 | Benign | 3.47 | Benign | 0.29 | Tolerated | 0.1330 | 0.5177 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1396T>A | S466T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S466T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Uncertain results come from Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, the SGM‑Consensus as Likely Benign, and Foldetta as Benign. Taken together, the majority of evidence points to a benign impact. Therefore, the variant is most likely benign, and this conclusion does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.311707 | Structured | 0.322353 | Uncertain | 0.933 | 0.227 | 0.000 | -5.488 | Likely Benign | 0.314 | Likely Benign | Likely Benign | 0.30 | Likely Benign | 0.2 | -1.02 | Ambiguous | -0.36 | Likely Benign | -0.65 | Ambiguous | 0.414 | Likely Benign | 1.05 | Neutral | 0.740 | Possibly Damaging | 0.872 | Possibly Damaging | -1.51 | Pathogenic | 1.00 | Tolerated | 0.0928 | 0.5152 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1401C>A | D467E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D467E is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (gnomAD ID: 6‑33438433‑C‑A). Prediction tools that agree on a benign effect include only FoldX. Tools that agree on a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (Likely Pathogenic). Uncertain or inconclusive predictions come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of reliable predictors indicate a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | 6-33438433-C-A | 2 | 1.24e-6 | -9.774 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.62 | Ambiguous | 0.60 | Ambiguous | 0.576 | Likely Pathogenic | -3.63 | Deleterious | 0.887 | Possibly Damaging | 0.938 | Probably Damaging | -1.08 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0.1061 | 0.4564 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||
| c.1401C>G | D467E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D467E missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain or inconclusive predictions come from Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the majority of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.268042 | Structured | 0.329932 | Uncertain | 0.940 | 0.246 | 0.000 | -9.774 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.1 | 0.87 | Ambiguous | 0.62 | Ambiguous | 0.60 | Ambiguous | 0.576 | Likely Pathogenic | -3.63 | Deleterious | 0.887 | Possibly Damaging | 0.938 | Probably Damaging | -1.08 | Pathogenic | 0.04 | Affected | 3.37 | 31 | 0.1061 | 0.4564 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.1411T>A | S471T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S471T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only FATHMM predicts pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign.” High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign; the SGM‑Consensus (3 benign vs. 1 pathogenic) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is benign. No prediction or stability result is inconclusive. Overall, the evidence overwhelmingly supports a benign classification, and this is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.305330 | Structured | 0.355411 | Uncertain | 0.888 | 0.261 | 0.000 | -5.780 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.59 | Ambiguous | 0.2 | -0.47 | Likely Benign | 0.06 | Likely Benign | 0.20 | Likely Benign | 0.257 | Likely Benign | -1.96 | Neutral | 0.000 | Benign | 0.000 | Benign | -1.18 | Pathogenic | 0.09 | Tolerated | 0.1307 | 0.5046 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1417G>A | V473I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473I is listed in ClinVar with an uncertain significance and is present in gnomAD (ID 6‑33438449‑G‑A). Functional prediction tools that agree on benign impact include REVEL, FoldX, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized. Pathogenic predictions are provided by both polyPhen‑2 HumDiv and HumVar. Predictions that are inconclusive are AlphaMissense‑Default, ESM1b, Foldetta, and Rosetta. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is unavailable due to no majority, and Foldetta is uncertain. Overall, the balance of evidence favors a benign effect for V473I, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | Uncertain | 1 | 6-33438449-G-A | 1 | 6.20e-7 | -7.481 | In-Between | 0.418 | Ambiguous | Likely Benign | -0.12 | Likely Benign | 0.0 | 1.20 | Ambiguous | 0.54 | Ambiguous | -0.06 | Likely Benign | 0.203 | Likely Benign | -0.91 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.74 | Benign | 0.18 | Tolerated | 3.37 | 34 | 0.0568 | 0.3335 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||
| c.1417G>C | V473L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and Foldetta, while those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools (seven pathogenic vs. six benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -9.073 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | -0.29 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.41 | Likely Benign | 0.35 | Likely Benign | 0.336 | Likely Benign | -2.85 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.43 | Benign | 0.21 | Tolerated | 0.0708 | 0.3921 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1417G>T | V473L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V473L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, SIFT, FATHMM, and Foldetta, while those that predict a pathogenic effect comprise SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), and Foldetta as benign. Overall, the majority of tools (seven pathogenic vs. six benign) indicate a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.191378 | Structured | 0.362529 | Uncertain | 0.884 | 0.239 | 0.000 | -9.073 | Likely Pathogenic | 0.966 | Likely Pathogenic | Likely Pathogenic | -0.29 | Likely Benign | 0.1 | -0.52 | Ambiguous | -0.41 | Likely Benign | 0.35 | Likely Benign | 0.335 | Likely Benign | -2.85 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | 3.43 | Benign | 0.21 | Tolerated | 0.0708 | 0.3921 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1422C>A | D474E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D474E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT, whereas a separate group predicts pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default. Two tools are uncertain: ESM1b and AlphaMissense‑Optimized. High‑accuracy assessments show SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, AlphaMissense‑Optimized as Uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the majority of predictions lean toward pathogenicity, but the high‑accuracy tools provide conflicting evidence. Thus, the variant is most likely pathogenic based on the current computational predictions, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -7.079 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.15 | Likely Benign | 0.10 | Likely Benign | 0.408 | Likely Benign | -3.01 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -1.11 | Pathogenic | 0.20 | Tolerated | 0.1233 | 0.4287 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1422C>G | D474E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D474E is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT, while those that agree on a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Two tools—AlphaMissense‑Optimized and ESM1b—return uncertain results. High‑accuracy assessments show SGM‑Consensus predicting a likely pathogenic outcome, AlphaMissense‑Optimized remaining uncertain, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicting a benign effect. Overall, the majority of consensus tools lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.102787 | Structured | 0.373433 | Uncertain | 0.864 | 0.255 | 0.000 | -7.079 | In-Between | 0.874 | Likely Pathogenic | Ambiguous | -0.35 | Likely Benign | 0.1 | 0.05 | Likely Benign | -0.15 | Likely Benign | 0.10 | Likely Benign | 0.408 | Likely Benign | -3.01 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -1.11 | Pathogenic | 0.20 | Tolerated | 0.1233 | 0.4287 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1505G>C | G502A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G502A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from Foldetta, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Optimized; pathogenic predictions arise from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Rosetta, and premPS. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized indicates a benign effect, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—concludes pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts a benign outcome. Overall, the majority of evidence points to a pathogenic impact for G502A, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.083462 | Structured | 0.340113 | Uncertain | 0.882 | 0.152 | 0.000 | -10.191 | Likely Pathogenic | 0.607 | Likely Pathogenic | Likely Benign | 0.82 | Ambiguous | 0.4 | -0.53 | Ambiguous | 0.15 | Likely Benign | 0.54 | Ambiguous | 0.725 | Likely Pathogenic | -5.64 | Deleterious | 0.512 | Possibly Damaging | 0.157 | Benign | -1.59 | Pathogenic | 0.17 | Tolerated | 0.3548 | 0.3393 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1524T>A | D508E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D508E is reported in gnomAD (ID 6‑33438556‑T‑A) and has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, FoldX, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the protein‑stability method Foldetta. Only PROVEAN predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign. Overall, the majority of evidence points to a benign effect, and this is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | 6-33438556-T-A | 1 | 6.20e-7 | -5.959 | Likely Benign | 0.242 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 0.1766 | 0.4304 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||
| c.1524T>G | D508E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D508E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign) all classify the change as benign. Only PROVEAN predicts a pathogenic outcome, while Rosetta and premPS are inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized reports benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also indicates benign stability. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.019401 | Structured | 0.255890 | Uncertain | 0.890 | 0.228 | 0.000 | -5.959 | Likely Benign | 0.242 | Likely Benign | Likely Benign | -0.39 | Likely Benign | 0.1 | 0.99 | Ambiguous | 0.30 | Likely Benign | 0.59 | Ambiguous | 0.118 | Likely Benign | -3.16 | Deleterious | 0.005 | Benign | 0.006 | Benign | 3.43 | Benign | 0.20 | Tolerated | 3.37 | 35 | 0.1766 | 0.4304 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||
| c.1532G>C | G511A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G511A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported by FoldX, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is inconclusive, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta remains uncertain. Overall, the balance of evidence (seven pathogenic versus three benign predictions) indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.244404 | Uncertain | 0.924 | 0.287 | 0.000 | -9.621 | Likely Pathogenic | 0.844 | Likely Pathogenic | Ambiguous | 0.80 | Ambiguous | 0.2 | 0.25 | Likely Benign | 0.53 | Ambiguous | 0.55 | Ambiguous | 0.275 | Likely Benign | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.998 | Probably Damaging | 3.23 | Benign | 0.02 | Affected | 0.3793 | 0.2778 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.154T>A | S52T 2D AIThe SynGAP1 missense variant S52T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumVar and SIFT. The high‑accuracy consensus (SGM‑Consensus, derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign impact, and this assessment does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.291804 | Structured | 0.457753 | Uncertain | 0.499 | 0.677 | 0.000 | -5.731 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.070 | Likely Benign | 0.06 | Neutral | 0.140 | Benign | 0.481 | Possibly Damaging | 4.33 | Benign | 0.00 | Affected | 0.1505 | 0.6751 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1558T>A | S520T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S520T is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from premPS and PROVEAN, while pathogenic predictions are made by SGM‑Consensus, REVEL, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. Four high‑accuracy methods were examined: AlphaMissense‑Optimized returned an uncertain result; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, was also uncertain. With three of the four high‑accuracy tools indicating pathogenicity and only two tools suggesting benign, the overall evidence points to a pathogenic effect. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.084894 | Uncertain | 0.887 | 0.337 | 0.000 | -8.432 | Likely Pathogenic | 0.822 | Likely Pathogenic | Ambiguous | 0.52 | Ambiguous | 0.0 | 0.52 | Ambiguous | 0.52 | Ambiguous | 0.34 | Likely Benign | 0.565 | Likely Pathogenic | -2.41 | Neutral | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | -1.28 | Pathogenic | 0.02 | Affected | 0.1296 | 0.5199 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1576G>A | V526I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V526I variant is not reported in ClinVar (ClinVar status: not listed) but is present in gnomAD (gnomAD ID: 6‑33438819‑G‑A). Prediction tools that agree on a benign effect include FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as benign. Overall, the majority of tools (seven benign vs. five pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for V526I. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | 6-33438819-G-A | -9.962 | Likely Pathogenic | 0.526 | Ambiguous | Likely Benign | 0.07 | Likely Benign | 0.3 | 0.41 | Likely Benign | 0.24 | Likely Benign | 0.02 | Likely Benign | 0.540 | Likely Pathogenic | -0.99 | Neutral | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | -1.34 | Pathogenic | 0.15 | Tolerated | 3.37 | 35 | 0.0630 | 0.3307 | 3 | 4 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.1576G>C | V526L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V526L, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -9.289 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.5 | 1.74 | Ambiguous | 1.53 | Ambiguous | 0.38 | Likely Benign | 0.643 | Likely Pathogenic | -2.97 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | -1.16 | Pathogenic | 0.17 | Tolerated | 0.0754 | 0.3894 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1576G>T | V526L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V526L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include premPS and SIFT, whereas the majority of algorithms—SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the change as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive results and are treated as unavailable evidence. High‑accuracy assessments reinforce the pathogenic prediction: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates pathogenicity; Foldetta remains uncertain. Overall, the preponderance of evidence points to a pathogenic effect for V526L, and this conclusion does not contradict the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.023118 | Uncertain | 0.943 | 0.403 | 0.000 | -9.289 | Likely Pathogenic | 0.982 | Likely Pathogenic | Likely Pathogenic | 1.31 | Ambiguous | 0.5 | 1.74 | Ambiguous | 1.53 | Ambiguous | 0.38 | Likely Benign | 0.643 | Likely Pathogenic | -2.97 | Deleterious | 0.929 | Possibly Damaging | 0.917 | Probably Damaging | -1.16 | Pathogenic | 0.17 | Tolerated | 0.0754 | 0.3894 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1581C>A | D527E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a deleterious effect, whereas only FoldX and premPS predict a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains Likely Pathogenic. Overall, the preponderance of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -11.125 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.8 | 2.29 | Destabilizing | 1.33 | Ambiguous | 0.50 | Likely Benign | 0.740 | Likely Pathogenic | -3.74 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -2.31 | Pathogenic | 0.02 | Affected | 0.1103 | 0.3428 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1581C>G | D527E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D527E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a strong bias toward pathogenicity: REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default all predict a deleterious effect, whereas only FoldX and premPS predict a benign outcome. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is inconclusive, Foldetta (combining FoldX‑MD and Rosetta outputs) is uncertain, and the SGM Consensus remains Likely Pathogenic. Overall, the preponderance of evidence points to a pathogenic impact, and this assessment does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.021908 | Uncertain | 0.913 | 0.408 | 0.000 | -11.125 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | 0.36 | Likely Benign | 0.8 | 2.29 | Destabilizing | 1.33 | Ambiguous | 0.50 | Likely Benign | 0.740 | Likely Pathogenic | -3.74 | Deleterious | 0.929 | Possibly Damaging | 0.938 | Probably Damaging | -2.31 | Pathogenic | 0.02 | Affected | 0.1103 | 0.3428 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.158G>C | G53A 2D AIThe SynGAP1 missense variant G53A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus (majority vote) also as 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 because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.268042 | Structured | 0.460894 | Uncertain | 0.386 | 0.666 | 0.000 | -6.329 | Likely Benign | 0.616 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -1.00 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 4.16 | Benign | 0.00 | Affected | 0.4093 | 0.5550 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1600T>A | S534T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S534T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, 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) predicts benign stability. Thus, the overall evidence strongly supports a benign classification, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.167087 | Structured | 0.032173 | Uncertain | 0.860 | 0.362 | 0.000 | -4.925 | Likely Benign | 0.104 | Likely Benign | Likely Benign | 0.10 | Likely Benign | 0.1 | 0.46 | Likely Benign | 0.28 | Likely Benign | 0.19 | Likely Benign | 0.200 | Likely Benign | -2.42 | Neutral | 0.676 | Possibly Damaging | 0.933 | Probably Damaging | 3.32 | Benign | 0.07 | Tolerated | 0.1238 | 0.5064 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1604G>C | S535T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S535T is catalogued in ClinVar as benign (ClinVar ID 537005.0) and is observed in gnomAD (variant ID 6‑33438847‑G‑C). In silico 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 return benign scores. Only FATHMM 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 confirm this: AlphaMissense‑Optimized is benign; the SGM Consensus is likely benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a benign effect. Overall, the consensus of predictive tools and high‑accuracy methods indicates that the variant is most likely benign, consistent with its ClinVar classification and presence in gnomAD. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.236433 | Structured | 0.041365 | Uncertain | 0.918 | 0.343 | 0.000 | Benign | 1 | 6-33438847-G-C | 14 | 8.67e-6 | -3.886 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.45 | Likely Benign | 0.1 | -0.27 | Likely Benign | 0.09 | Likely Benign | 0.17 | Likely Benign | 0.177 | Likely Benign | -0.81 | Neutral | 0.000 | Benign | 0.001 | Benign | -1.25 | Pathogenic | 0.25 | Tolerated | 3.37 | 35 | 0.1456 | 0.6291 | 1 | 1 | 0.1 | 14.03 | 201.3 | -17.3 | -0.1 | 0.7 | -0.2 | 0.1 | X | Potentially Benign | Ser535 is located near the terminal end of an α-helix (res. Ala533-Val560) close to the membrane interface. In the WT simulations, the hydroxyl side chain of Ser535 forms hydrogen bonds with nearby residues (e.g., His539, Glu538) without any specific interactions. These hydrogen bonds disrupt the structure of the terminal end of the α-helix (Ala533-Ser535), causing it to weaken or unfold during the WT simulations. In the variant simulations, Thr535, a hydrophilic residue with a hydroxyl group of almost the same size as Ser, interacts more frequently with the preceding loop residues (e.g., Thr532, Cys531) due to its longer side chain. Regardless, the residue swap is tolerated in the simulations with no negative effects. However, due to its location near the SynGAP-membrane interface, the effect of the residue swap cannot be fully addressed using the SynGAP solvent-only simulations. | 10.1016/j.ajhg.2020.11.011 | ||||||||||||
| c.1660G>C | V554L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome, while FoldX, premPS, and ESM1b are uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the available computational evidence, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -7.884 | In-Between | 0.645 | Likely Pathogenic | Likely Benign | -1.14 | Ambiguous | 0.0 | 0.29 | Likely Benign | -0.43 | Likely Benign | 0.56 | Ambiguous | 0.162 | Likely Benign | -1.54 | Neutral | 0.204 | Benign | 0.053 | Benign | 3.49 | Benign | 0.08 | Tolerated | 0.0991 | 0.2998 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1660G>T | V554L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V554L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only AlphaMissense‑Default predicts a pathogenic outcome, while FoldX, premPS, and ESM1b are uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign consensus; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. No prediction or stability result is missing or inconclusive. Overall, the variant is most likely benign based on the available computational evidence, and this conclusion is not contradicted by any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.020522 | Structured | 0.007349 | Uncertain | 0.955 | 0.226 | 0.000 | -7.884 | In-Between | 0.645 | Likely Pathogenic | Likely Benign | -1.14 | Ambiguous | 0.0 | 0.29 | Likely Benign | -0.43 | Likely Benign | 0.56 | Ambiguous | 0.162 | Likely Benign | -1.54 | Neutral | 0.204 | Benign | 0.053 | Benign | 3.49 | Benign | 0.08 | Tolerated | 0.0991 | 0.2998 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1663G>A | V555I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V555I is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Prediction tools that uniformly indicate a benign effect include REVEL, Rosetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only FATHMM predicts a pathogenic outcome, while FoldX, Foldetta, and premPS are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Benign, and Foldetta as uncertain. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | Uncertain | 1 | -4.544 | Likely Benign | 0.084 | Likely Benign | Likely Benign | -0.82 | Ambiguous | 0.0 | -0.41 | Likely Benign | -0.62 | Ambiguous | -0.55 | Ambiguous | 0.253 | Likely Benign | 0.45 | Neutral | 0.002 | Benign | 0.002 | Benign | -1.26 | Pathogenic | 1.00 | Tolerated | 0.0844 | 0.2590 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||
| c.1663G>C | V555L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V555L is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The remaining tools—FoldX, Foldetta, ESM1b, and AlphaMissense‑Default—return uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is unavailable due to a tie between pathogenic and benign calls, and Foldetta is uncertain. Overall, the preponderance of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.013265 | Structured | 0.008218 | Uncertain | 0.943 | 0.225 | 0.000 | -7.816 | In-Between | 0.521 | Ambiguous | Likely Benign | -1.43 | Ambiguous | 0.1 | -0.14 | Likely Benign | -0.79 | Ambiguous | 0.16 | Likely Benign | 0.260 | Likely Benign | -0.97 | Neutral | 0.025 | Benign | 0.015 | Benign | -1.22 | Pathogenic | 0.14 | Tolerated | 0.1036 | 0.2958 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.1669T>A | S557T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S557T is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include premPS, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic effect comprise REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Predictions that are uncertain (AlphaMissense‑Default and Foldetta) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM Consensus as pathogenic, and Foldetta as uncertain. Overall, the majority of available predictions indicate a pathogenic impact. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.028107 | Structured | 0.010261 | Uncertain | 0.924 | 0.215 | 0.000 | -9.089 | Likely Pathogenic | 0.418 | Ambiguous | Likely Benign | 2.14 | Destabilizing | 0.2 | 0.40 | Likely Benign | 1.27 | Ambiguous | 0.21 | Likely Benign | 0.744 | Likely Pathogenic | -2.53 | Deleterious | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | -1.64 | Pathogenic | 0.07 | Tolerated | 0.1514 | 0.6336 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1678G>C | V560L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V560L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, AlphaMissense‑Optimized, and Foldetta; pathogenic predictions come from polyPhen‑2 HumDiv, ESM1b, and FATHMM. AlphaMissense‑Default remains uncertain. High‑accuracy assessments further refine the picture: AlphaMissense‑Optimized predicts benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic (2 pathogenic vs. 1 benign). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, also predicts benign. Overall, the bulk of evidence points to a benign effect, but the SGM Consensus and the presence of pathogenic signals from several high‑confidence tools introduce uncertainty. Thus, the variant is most likely benign based on the prevailing predictions, and this assessment does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | -10.191 | Likely Pathogenic | 0.533 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.0 | 0.48 | Likely Benign | 0.02 | Likely Benign | 0.45 | Likely Benign | 0.489 | Likely Benign | -2.45 | Neutral | 0.508 | Possibly Damaging | 0.209 | Benign | -1.24 | Pathogenic | 0.40 | Tolerated | 3.37 | 35 | 0.1430 | 0.4162 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||
| c.1678G>T | V560L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V560L variant has no ClinVar entry (ClinVar status: None) but is catalogued in gnomAD (ID 6‑33440730‑G‑T). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, PROVEAN, SIFT, and AlphaMissense‑Optimized. Those that predict a pathogenic impact are polyPhen‑2 HumDiv, ESM1b, and FATHMM (polyPhen‑2 HumVar is benign, AlphaMissense‑Default is uncertain). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) leaning pathogenic (2 pathogenic vs 1 benign), and Foldetta indicating a benign stability change. Overall, the majority of conventional tools favor a benign classification, yet the high‑accuracy consensus and Foldetta suggest a pathogenic signal. Based on the most reliable predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.021381 | Structured | 0.013872 | Uncertain | 0.853 | 0.204 | 0.000 | 6-33440730-G-T | 1 | 6.34e-7 | -10.191 | Likely Pathogenic | 0.533 | Ambiguous | Likely Benign | -0.44 | Likely Benign | 0.0 | 0.48 | Likely Benign | 0.02 | Likely Benign | 0.45 | Likely Benign | 0.489 | Likely Benign | -2.45 | Neutral | 0.508 | Possibly Damaging | 0.209 | Benign | -1.24 | Pathogenic | 0.40 | Tolerated | 3.37 | 35 | 0.1430 | 0.4162 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1702G>C | V568L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V568L variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include FoldX, Foldetta, and polyPhen‑2 HumVar, while those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus (which itself is a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Uncertain predictions come from Rosetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools predict a pathogenic impact, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.053503 | Uncertain | 0.937 | 0.257 | 0.000 | -9.503 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | -0.30 | Likely Benign | 0.3 | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.56 | Ambiguous | 0.651 | Likely Pathogenic | -2.69 | Deleterious | 0.511 | Possibly Damaging | 0.147 | Benign | -1.23 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.0944 | 0.3312 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||
| c.1702G>T | V568L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V568L is listed in ClinVar with an “Uncertain” status and is not reported in gnomAD. Among the available in‑silico predictors, eight tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic effect, whereas three tools (FoldX, Foldetta, and polyPhen‑2 HumVar) predict a benign outcome; the remaining three (Rosetta, premPS, AlphaMissense‑Optimized) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta stability outputs) as benign. Overall, the preponderance of evidence points to a pathogenic impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.024826 | Structured | 0.053503 | Uncertain | 0.937 | 0.257 | 0.000 | Uncertain | 1 | -9.503 | Likely Pathogenic | 0.921 | Likely Pathogenic | Ambiguous | -0.30 | Likely Benign | 0.3 | 0.57 | Ambiguous | 0.14 | Likely Benign | 0.56 | Ambiguous | 0.651 | Likely Pathogenic | -2.69 | Deleterious | 0.511 | Possibly Damaging | 0.147 | Benign | -1.23 | Pathogenic | 0.04 | Affected | 3.37 | 35 | 0.0944 | 0.3312 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||
| c.1711T>A | S571T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S571T 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 FoldX, Rosetta, Foldetta, premPS, SIFT, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools (seven) predict pathogenicity, while six predict benignity, and the high‑accuracy subset is split. Thus, the variant is most likely pathogenic based on the prevailing 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. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.045569 | Uncertain | 0.928 | 0.270 | 0.000 | -8.243 | Likely Pathogenic | 0.431 | Ambiguous | Likely Benign | 0.37 | Likely Benign | 0.1 | -0.21 | Likely Benign | 0.08 | Likely Benign | 0.25 | Likely Benign | 0.564 | Likely Pathogenic | -2.76 | Deleterious | 0.933 | Possibly Damaging | 0.933 | Probably Damaging | -1.25 | Pathogenic | 0.10 | Tolerated | 0.1360 | 0.4014 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1739G>C | G580A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G580A is not reported in ClinVar (ClinVar status: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity are unanimous: REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus all predict a deleterious effect. Tools with uncertain or inconclusive results (Rosetta and premPS) are noted as unavailable for pathogenicity inference. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized reports Pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic; and Foldetta, a protein‑folding stability predictor that integrates FoldX‑MD and Rosetta outputs, also classifies the variant as Pathogenic. Consequently, the variant is most likely pathogenic based on the consensus of predictive tools, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.104810 | Structured | 0.025952 | Uncertain | 0.853 | 0.236 | 0.000 | -10.841 | Likely Pathogenic | 0.956 | Likely Pathogenic | Likely Pathogenic | 2.84 | Destabilizing | 0.1 | 1.55 | Ambiguous | 2.20 | Destabilizing | 0.64 | Ambiguous | 0.646 | Likely Pathogenic | -5.73 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | -1.22 | Pathogenic | 0.05 | Affected | 0.3657 | 0.2862 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1749C>A | D583E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D583E missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT. Those that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and ESM1b. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign, and AlphaMissense‑Optimized as Uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -7.861 | In-Between | 0.851 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.2 | -0.36 | Likely Benign | -0.06 | Likely Benign | -0.20 | Likely Benign | 0.467 | Likely Benign | -3.52 | Deleterious | 0.960 | Probably Damaging | 0.969 | Probably Damaging | -1.18 | Pathogenic | 0.12 | Tolerated | 0.1200 | 0.4037 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1749C>G | D583E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D583E missense variant is not reported in ClinVar (ClinVar ID None) and has no entry in gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, premPS, and SIFT. Those that predict a pathogenic effect are SGM‑Consensus (Likely Pathogenic), PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. Two tools give uncertain results: AlphaMissense‑Optimized and ESM1b. High‑accuracy assessments show SGM‑Consensus as Likely Pathogenic, Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign, and AlphaMissense‑Optimized as Uncertain. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.116183 | Structured | 0.038478 | Uncertain | 0.805 | 0.247 | 0.000 | -7.861 | In-Between | 0.851 | Likely Pathogenic | Ambiguous | 0.25 | Likely Benign | 0.2 | -0.36 | Likely Benign | -0.06 | Likely Benign | -0.20 | Likely Benign | 0.466 | Likely Benign | -3.52 | Deleterious | 0.960 | Probably Damaging | 0.969 | Probably Damaging | -1.18 | Pathogenic | 0.12 | Tolerated | 0.1200 | 0.4037 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1758C>A | D586E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586E 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, ESM1b, AlphaMissense‑Optimized, and Foldetta. Those that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Default; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split. Overall, the majority of evidence points to a benign effect. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -3.233 | Likely Benign | 0.683 | Likely Pathogenic | Likely Benign | -0.42 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.23 | Likely Benign | 0.38 | Likely Benign | 0.367 | Likely Benign | -0.12 | Neutral | 0.929 | Possibly Damaging | 0.969 | Probably Damaging | -1.20 | Pathogenic | 1.00 | Tolerated | 0.1304 | 0.5126 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1758C>G | D586E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D586E 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, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default; Rosetta is 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 evidence points to a benign impact. This conclusion does not contradict ClinVar status, as no ClinVar assertion exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.060549 | Structured | 0.066018 | Uncertain | 0.866 | 0.241 | 0.000 | -3.233 | Likely Benign | 0.683 | Likely Pathogenic | Likely Benign | -0.42 | Likely Benign | 0.1 | 0.88 | Ambiguous | 0.23 | Likely Benign | 0.38 | Likely Benign | 0.367 | Likely Benign | -0.12 | Neutral | 0.929 | Possibly Damaging | 0.969 | Probably Damaging | -1.20 | Pathogenic | 1.00 | Tolerated | 0.1304 | 0.5126 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.1769G>C | S590T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S590T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and ESM1b. Two tools (premPS and AlphaMissense‑Default) return uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.022667 | Structured | 0.088943 | Uncertain | 0.918 | 0.199 | 0.000 | -12.472 | Likely Pathogenic | 0.458 | Ambiguous | Likely Benign | 0.23 | Likely Benign | 0.1 | 0.42 | Likely Benign | 0.33 | Likely Benign | 0.64 | Ambiguous | 0.459 | Likely Benign | -2.89 | Deleterious | 0.183 | Benign | 0.050 | Benign | 3.15 | Benign | 0.08 | Tolerated | 0.1420 | 0.5723 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1774T>A | S592T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S592T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include Foldetta, SIFT, and AlphaMissense‑Optimized, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default) classify the change as pathogenic. High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized predicts a benign outcome, while the SGM Consensus—derived from a unanimous pathogenic vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—indicates pathogenicity; Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, also reports a benign effect. Predictions from FoldX, Rosetta, and premPS are inconclusive and are treated as unavailable. Overall, the preponderance of evidence from multiple independent predictors points to a pathogenic effect for S592T, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.012270 | Structured | 0.100070 | Uncertain | 0.913 | 0.182 | 0.000 | -11.670 | Likely Pathogenic | 0.677 | Likely Pathogenic | Likely Benign | 0.86 | Ambiguous | 0.1 | -0.88 | Ambiguous | -0.01 | Likely Benign | 0.61 | Ambiguous | 0.819 | Likely Pathogenic | -2.79 | Deleterious | 0.933 | Possibly Damaging | 0.933 | Probably Damaging | -1.26 | Pathogenic | 0.17 | Tolerated | 0.1531 | 0.4684 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.180T>A | D60E 2D AIThe SynGAP1 D60E missense variant has no ClinVar record and is not listed in gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.284882 | Structured | 0.480942 | Uncertain | 0.521 | 0.676 | 0.000 | -3.818 | Likely Benign | 0.780 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | -0.90 | Neutral | 0.643 | Possibly Damaging | 0.785 | Possibly Damaging | 4.05 | Benign | 0.00 | Affected | 0.1342 | 0.7869 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.180T>G | D60E 2D AIThe SynGAP1 D60E 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 SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also resolves to benign. Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.284882 | Structured | 0.480942 | Uncertain | 0.521 | 0.676 | 0.000 | -3.818 | Likely Benign | 0.780 | Likely Pathogenic | Likely Benign | 0.089 | Likely Benign | -0.90 | Neutral | 0.643 | Possibly Damaging | 0.785 | Possibly Damaging | 4.05 | Benign | 0.00 | Affected | 0.1342 | 0.7869 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1810T>A | S604T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S604T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Foldetta, premPS, SIFT, and FATHMM, while those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Predictions that are uncertain or inconclusive (FoldX, Rosetta, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall pattern of predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.010926 | Structured | 0.192527 | Uncertain | 0.911 | 0.195 | 0.000 | -9.674 | Likely Pathogenic | 0.897 | Likely Pathogenic | Ambiguous | 0.64 | Ambiguous | 0.1 | -0.58 | Ambiguous | 0.03 | Likely Benign | -0.16 | Likely Benign | 0.337 | Likely Benign | -2.99 | Deleterious | 0.826 | Possibly Damaging | 0.872 | Possibly Damaging | 3.19 | Benign | 0.08 | Tolerated | 0.1687 | 0.4919 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1817G>C | S606T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S606T is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, FATHMM, and AlphaMissense‑Optimized, whereas a pathogenic consensus is reached by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. Uncertain results come from Rosetta, premPS, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools predict pathogenicity, and the SGM Consensus supports this view, while the high‑accuracy methods give mixed results. Thus, the variant is most likely pathogenic based on the available predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.041405 | Structured | 0.191720 | Uncertain | 0.875 | 0.247 | 0.000 | -11.052 | Likely Pathogenic | 0.554 | Ambiguous | Likely Benign | 0.06 | Likely Benign | 0.1 | -0.91 | Ambiguous | -0.43 | Likely Benign | 0.57 | Ambiguous | 0.203 | Likely Benign | -2.99 | Deleterious | 0.826 | Possibly Damaging | 0.933 | Probably Damaging | 3.34 | Benign | 0.03 | Affected | 0.1260 | 0.4513 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||
| c.1826G>C | G609A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G609A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, Rosetta, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are FoldX, PROVEAN, and FATHMM. One tool, Foldetta, yields an uncertain result. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta remains uncertain. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.179055 | Structured | 0.203786 | Uncertain | 0.851 | 0.252 | 0.000 | -6.790 | Likely Benign | 0.153 | Likely Benign | Likely Benign | 2.38 | Destabilizing | 0.3 | 0.01 | Likely Benign | 1.20 | Ambiguous | 0.43 | Likely Benign | 0.494 | Likely Benign | -2.65 | Deleterious | 0.282 | Benign | 0.164 | Benign | -1.43 | Pathogenic | 0.10 | Tolerated | 0.3812 | 0.3896 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.1848T>A | D616E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D616E missense variant is catalogued in gnomAD (ID 6‑33440900‑T‑A) but has no ClinVar submission. Functional prediction tools show a split assessment: benign calls come from REVEL, both polyPhen‑2 HumDiv and HumVar, FATHMM, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, SIFT, and AlphaMissense‑Default. The remaining predictors (FoldX, Rosetta, Foldetta, premPS, ESM1b) are inconclusive. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized remains benign, and Foldetta, which evaluates protein‑folding stability, is uncertain. Overall, the majority of evidence leans toward pathogenicity, and this conclusion does not conflict with ClinVar because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | 6-33440900-T-A | 1 | 6.20e-7 | -7.250 | In-Between | 0.695 | Likely Pathogenic | Likely Benign | 0.96 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.24 | Ambiguous | 0.58 | Ambiguous | 0.092 | Likely Benign | -2.85 | Deleterious | 0.421 | Benign | 0.232 | Benign | 3.32 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1225 | 0.4128 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1848T>G | D616E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D616E is not reported in ClinVar but is present in gnomAD (ID 6‑33440900‑T‑G). Functional prediction tools that agree on benign impact include REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Optimized. Those that predict pathogenicity are PROVEAN, SIFT, and AlphaMissense‑Default. The remaining tools (FoldX, Rosetta, Foldetta, premPS, ESM1b) are inconclusive. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as pathogenic, and Foldetta as uncertain. Overall, the majority of conventional predictors lean toward a benign effect, but the high‑accuracy consensus is split, leaving the variant’s clinical significance unresolved. Thus, the variant is most likely benign based on the bulk of predictions, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.129801 | Structured | 0.166689 | Uncertain | 0.867 | 0.252 | 0.000 | 6-33440900-T-G | 3 | 1.86e-6 | -7.250 | In-Between | 0.695 | Likely Pathogenic | Likely Benign | 0.96 | Ambiguous | 0.1 | 1.52 | Ambiguous | 1.24 | Ambiguous | 0.58 | Ambiguous | 0.092 | Likely Benign | -2.85 | Deleterious | 0.421 | Benign | 0.232 | Benign | 3.32 | Benign | 0.03 | Affected | 3.37 | 35 | 0.1225 | 0.4128 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||
| c.1858T>A | S620T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S620T has no ClinVar entry and is not reported in gnomAD. Prediction tools that classify it as benign include Foldetta, premPS, PROVEAN, SIFT, AlphaMissense‑Optimized, and Rosetta. Those that predict pathogenicity are SGM‑Consensus, REVEL, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized labeling the variant as benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicating likely pathogenic, and Foldetta predicting benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of tools lean toward a pathogenic effect, and this assessment does not contradict the ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.139895 | Structured | 0.100377 | Uncertain | 0.936 | 0.219 | 0.000 | -9.171 | Likely Pathogenic | 0.660 | Likely Pathogenic | Likely Benign | 0.52 | Ambiguous | 0.1 | -0.40 | Likely Benign | 0.06 | Likely Benign | 0.30 | Likely Benign | 0.551 | Likely Pathogenic | -1.99 | Neutral | 0.896 | Possibly Damaging | 0.933 | Probably Damaging | -1.25 | Pathogenic | 0.14 | Tolerated | 0.1288 | 0.5199 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.186T>A | D62E 2D AIThe SynGAP1 missense variant D62E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -2.653 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.19 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.49 | Benign | 0.00 | Affected | 0.1884 | 0.5800 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.186T>G | D62E 2D AIThe SynGAP1 missense variant D62E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta, has no available result for this variant. Overall, the consensus of the majority of tools and the high‑accuracy predictions point to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.425610 | Structured | 0.476010 | Uncertain | 0.575 | 0.720 | 0.125 | -2.653 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.065 | Likely Benign | -0.19 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.49 | Benign | 0.00 | Affected | 0.1884 | 0.5800 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.1885G>A | V629I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629I is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, AlphaMissense‑Optimized, and FATHMM. Those that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar) and SIFT, with ESM1b also indicating pathogenicity. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) resolves to benign, and Foldetta also predicts a benign outcome. Taken together, the preponderance of evidence supports a benign classification for V629I, and this conclusion does not contradict the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -9.876 | Likely Pathogenic | 0.462 | Ambiguous | Likely Benign | -0.22 | Likely Benign | 0.1 | 0.37 | Likely Benign | 0.08 | Likely Benign | 0.21 | Likely Benign | 0.305 | Likely Benign | -1.00 | Neutral | 0.975 | Probably Damaging | 0.958 | Probably Damaging | 3.26 | Benign | 0.04 | Affected | 0.0650 | 0.2919 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||
| c.1885G>C | V629L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V629L has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate a benign effect include REVEL, FoldX, and FATHMM, whereas the majority of algorithms predict a pathogenic outcome: Rosetta, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools report uncertainty: Foldetta and premPS. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely pathogenic. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus also indicates likely pathogenic, while Foldetta remains uncertain. Based on the collective evidence, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.040537 | Structured | 0.034796 | Uncertain | 0.970 | 0.236 | 0.000 | -12.785 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 0.06 | Likely Benign | 0.2 | 2.26 | Destabilizing | 1.16 | Ambiguous | 0.54 | Ambiguous | 0.391 | Likely Benign | -2.79 | Deleterious | 0.975 | Probably Damaging | 0.958 | Probably Damaging | 3.22 | Benign | 0.02 | Affected | 0.0805 | 0.3336 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||
| c.1909T>A | S637T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S637T 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, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is 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) indicates Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.076542 | Structured | 0.083482 | Uncertain | 0.920 | 0.253 | 0.000 | -4.116 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.36 | Likely Benign | 0.1 | -0.91 | Ambiguous | -0.28 | Likely Benign | -0.39 | Likely Benign | 0.067 | Likely Benign | -0.19 | Neutral | 0.086 | Benign | 0.019 | Benign | 3.45 | Benign | 0.19 | Tolerated | 0.1675 | 0.4572 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1921T>A | S641T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S641T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly indicate a benign effect: REVEL, premPS, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, PROVEAN, AlphaMissense‑Default, and AlphaMissense‑Optimized all score the variant as benign. Rosetta also predicts a benign outcome, while FoldX and Foldetta are inconclusive (marked “Uncertain”). No tool predicts pathogenicity. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; Foldetta remains uncertain. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.125101 | Structured | 0.157322 | Uncertain | 0.786 | 0.270 | 0.000 | -6.637 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.83 | Ambiguous | 0.3 | 0.41 | Likely Benign | 0.62 | Ambiguous | 0.13 | Likely Benign | 0.043 | Likely Benign | -1.50 | Neutral | 0.008 | Benign | 0.003 | Benign | 3.39 | Benign | 0.09 | Tolerated | 0.1505 | 0.5888 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.1932C>A | D644E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D644E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments confirm a benign impact: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -1.778 | Likely Benign | 0.178 | Likely Benign | Likely Benign | -0.17 | Likely Benign | 0.1 | -0.51 | Ambiguous | -0.34 | Likely Benign | -0.47 | Likely Benign | 0.132 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.55 | Benign | 1.00 | Tolerated | 0.1528 | 0.6186 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1932C>G | D644E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D644E is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts a pathogenic outcome; the only inconclusive result is from Rosetta, which is treated as unavailable. High‑accuracy assessments confirm a benign impact: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.066181 | Structured | 0.248888 | Uncertain | 0.883 | 0.320 | 0.000 | -1.778 | Likely Benign | 0.178 | Likely Benign | Likely Benign | -0.17 | Likely Benign | 0.1 | -0.51 | Ambiguous | -0.34 | Likely Benign | -0.47 | Likely Benign | 0.132 | Likely Benign | 1.31 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.55 | Benign | 1.00 | Tolerated | 0.1528 | 0.6186 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.1940G>C | G647A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G647A is not reported in ClinVar and is absent from gnomAD. Functional 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. Predictions that are inconclusive are 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 as Uncertain. Taken together, the overwhelming majority of evidence indicates a benign effect for G647A, 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 | GAP | 0.048328 | Structured | 0.325524 | Uncertain | 0.936 | 0.356 | 0.000 | -0.266 | Likely Benign | 0.078 | Likely Benign | Likely Benign | -0.18 | Likely Benign | 0.0 | -0.99 | Ambiguous | -0.59 | Ambiguous | -0.69 | Ambiguous | 0.037 | Likely Benign | 0.48 | Neutral | 0.000 | Benign | 0.002 | Benign | 3.55 | Benign | 0.81 | Tolerated | 0.3558 | 0.4136 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1973G>C | G658A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G658A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools uniformly classify the substitution as benign: REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a neutral effect, and the SGM‑Consensus score indicates a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments corroborate this view: AlphaMissense‑Optimized returns a benign prediction, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also reports a likely benign result, while Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, yields an uncertain outcome. Taken together, the evidence overwhelmingly supports a benign impact for G658A, and this conclusion does not conflict with the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.029376 | Structured | 0.180299 | Uncertain | 0.942 | 0.251 | 0.000 | -4.303 | Likely Benign | 0.083 | Likely Benign | Likely Benign | -0.34 | Likely Benign | 0.0 | -0.75 | Ambiguous | -0.55 | Ambiguous | -0.18 | Likely Benign | 0.072 | Likely Benign | -0.93 | Neutral | 0.002 | Benign | 0.001 | Benign | 3.47 | Benign | 0.36 | Tolerated | 0.3937 | 0.3352 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.1975T>A | S659T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S659T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, FATHMM, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign. Only Rosetta reports an uncertain outcome, which is treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No tool predicts pathogenicity. Consequently, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.067594 | Structured | 0.154597 | Uncertain | 0.954 | 0.283 | 0.000 | -5.693 | Likely Benign | 0.157 | Likely Benign | Likely Benign | -0.15 | Likely Benign | 0.0 | -0.74 | Ambiguous | -0.45 | Likely Benign | 0.42 | Likely Benign | 0.106 | Likely Benign | -2.04 | Neutral | 0.069 | Benign | 0.011 | Benign | 3.41 | Benign | 0.39 | Tolerated | 0.1505 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.19T>A | S7T 2D AIThe SynGAP1 missense variant S7T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.590140 | Disordered | 0.548467 | Binding | 0.386 | 0.922 | 0.750 | -4.182 | Likely Benign | 0.110 | Likely Benign | Likely Benign | 0.101 | Likely Benign | -0.26 | Neutral | 0.024 | Benign | 0.007 | Benign | 4.13 | Benign | 0.00 | Affected | 0.1688 | 0.5919 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2002T>A | S668T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S668T is not reported in ClinVar (ClinVar ID: None) and has no entries in gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, premPS, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Tools that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely pathogenic outcome; Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. No evidence from FoldX or Rosetta alone is conclusive. Overall, the balance of predictions leans toward pathogenicity, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.247041 | Structured | 0.084935 | Uncertain | 0.922 | 0.370 | 0.000 | -11.860 | Likely Pathogenic | 0.703 | Likely Pathogenic | Likely Benign | 1.73 | Ambiguous | 0.7 | 0.89 | Ambiguous | 1.31 | Ambiguous | 0.27 | Likely Benign | 0.238 | Likely Benign | -2.99 | Deleterious | 0.844 | Possibly Damaging | 0.198 | Benign | 3.24 | Benign | 0.02 | Affected | 0.1212 | 0.5918 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2013C>A | D671E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D671E is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools uniformly indicate a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the substitution as benign. The only inconclusive result is AlphaMissense‑Default, which is listed as uncertain; all other high‑accuracy predictors support a benign outcome. In particular, AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports Likely Benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also reports 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 annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -3.657 | Likely Benign | 0.371 | Ambiguous | Likely Benign | -0.17 | Likely Benign | 0.1 | 0.22 | Likely Benign | 0.03 | Likely Benign | 0.03 | Likely Benign | 0.066 | Likely Benign | -0.83 | Neutral | 0.013 | Benign | 0.009 | Benign | 3.47 | Benign | 0.53 | Tolerated | 0.1520 | 0.6388 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2013C>G | D671E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D671E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include SGM‑Consensus (Likely Benign), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome. The high‑accuracy assessments are consistent: AlphaMissense‑Optimized indicates 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 Benign. With all available evidence pointing to a benign effect and no ClinVar record to contradict this, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.096749 | Uncertain | 0.677 | 0.370 | 0.000 | -3.657 | Likely Benign | 0.371 | Ambiguous | Likely Benign | -0.17 | Likely Benign | 0.1 | 0.22 | Likely Benign | 0.03 | Likely Benign | 0.03 | Likely Benign | 0.066 | Likely Benign | -0.83 | Neutral | 0.013 | Benign | 0.009 | Benign | 3.47 | Benign | 0.53 | Tolerated | 0.1520 | 0.6388 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2027G>C | S676T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S676T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and 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 interpretation: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the consensus of available predictions indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.209395 | Structured | 0.113632 | Uncertain | 0.551 | 0.338 | 0.125 | -5.621 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.79 | Ambiguous | 0.1 | 0.34 | Likely Benign | 0.57 | Ambiguous | -0.36 | Likely Benign | 0.098 | Likely Benign | 0.91 | Neutral | 0.050 | Benign | 0.017 | Benign | 3.52 | Benign | 1.00 | Tolerated | 0.1575 | 0.6286 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2030G>C | S677T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S677T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree that the substitution is benign: SIFT, PolyPhen‑2 (HumDiv and HumVar), REVEL, PROVEAN, premPS, FoldX, AlphaMissense‑Default, AlphaMissense‑Optimized, ESM1b, and FATHMM all classify it as benign. No tool predicts pathogenicity. The only inconclusive results come from Rosetta (Uncertain) and Foldetta (Uncertain), which are treated as unavailable evidence. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and Foldetta remains Uncertain. Overall, the consensus of available predictions indicates that S677T is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.194234 | Structured | 0.115685 | Uncertain | 0.555 | 0.338 | 0.125 | -4.760 | Likely Benign | 0.063 | Likely Benign | Likely Benign | -0.17 | Likely Benign | 0.3 | -0.85 | Ambiguous | -0.51 | Ambiguous | 0.15 | Likely Benign | 0.070 | Likely Benign | -0.97 | Neutral | 0.008 | Benign | 0.007 | Benign | 3.32 | Benign | 0.30 | Tolerated | 0.1775 | 0.6985 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2033G>C | S678T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S678T is not reported in ClinVar and is absent from gnomAD. All available in‑silico predictors classify the change as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). No tool predicts pathogenicity. High‑accuracy assessments likewise support a benign effect: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Based on the unanimous computational evidence, the variant is most likely benign, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.301917 | Structured | 0.123585 | Uncertain | 0.660 | 0.321 | 0.000 | -5.389 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.32 | Likely Benign | 0.1 | 0.41 | Likely Benign | 0.37 | Likely Benign | 0.14 | Likely Benign | 0.053 | Likely Benign | -1.82 | Neutral | 0.255 | Benign | 0.053 | Benign | 3.41 | Benign | 0.11 | Tolerated | 0.1494 | 0.6351 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2042G>C | G681A 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant G681A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show mixed results: benign calls come from REVEL, polyPhen‑2 HumVar, SIFT, and FATHMM, while pathogenic calls are made by PROVEAN, polyPhen‑2 HumDiv, ESM1b, and AlphaMissense‑Default. Predictions labeled uncertain include FoldX, Rosetta, Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized remains uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as likely pathogenic; Foldetta, which integrates FoldX‑MD and Rosetta outputs, is also uncertain. Overall, the preponderance of evidence points to a pathogenic effect for G681A. This conclusion is not contradicted by ClinVar, which contains no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.301917 | Structured | 0.140647 | Uncertain | 0.694 | 0.320 | 0.000 | -11.958 | Likely Pathogenic | 0.836 | Likely Pathogenic | Ambiguous | 1.77 | Ambiguous | 1.0 | 0.89 | Ambiguous | 1.33 | Ambiguous | 0.68 | Ambiguous | 0.354 | Likely Benign | -5.99 | Deleterious | 0.968 | Probably Damaging | 0.427 | Benign | 3.41 | Benign | 0.07 | Tolerated | 0.3879 | 0.4401 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2052C>A | D684E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D684E missense variant has no ClinVar entry and is not reported in gnomAD. Functional prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. In contrast, a majority of predictors (SGM‑Consensus, FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact; predictions from Rosetta and premPS are inconclusive and are treated as unavailable. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -9.506 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.18 | Destabilizing | 0.66 | Ambiguous | 0.362 | Likely Benign | -3.99 | Deleterious | 0.910 | Possibly Damaging | 0.210 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1316 | 0.6187 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2052C>G | D684E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant D684E is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, polyPhen‑2 HumVar, and FATHMM, whereas the majority of algorithms predict a deleterious effect: FoldX, Foldetta, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Two methods (Rosetta and premPS) returned uncertain results. High‑accuracy assessments further support a damaging impact: AlphaMissense‑Optimized is pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. Overall, the computational evidence overwhelmingly indicates that D684E is pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.254060 | Structured | 0.153798 | Uncertain | 0.870 | 0.282 | 0.000 | -9.506 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.88 | Destabilizing | 0.9 | 1.48 | Ambiguous | 2.18 | Destabilizing | 0.66 | Ambiguous | 0.362 | Likely Benign | -3.99 | Deleterious | 0.910 | Possibly Damaging | 0.210 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1316 | 0.6187 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.2057G>C | G686A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G686A is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify it as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, whereas pathogenic predictions come from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; premPS is uncertain. High‑accuracy methods give a pathogenic verdict from AlphaMissense‑Optimized and a Likely Pathogenic consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while Foldetta predicts benign stability. Overall, the majority of evidence points to a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.109221 | Structured | 0.177104 | Uncertain | 0.919 | 0.268 | 0.000 | -9.975 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.39 | Likely Benign | 0.2 | -0.46 | Likely Benign | -0.43 | Likely Benign | 0.58 | Ambiguous | 0.321 | Likely Benign | -5.19 | Deleterious | 0.993 | Probably Damaging | 0.732 | Possibly Damaging | 3.37 | Benign | 0.13 | Tolerated | 0.3744 | 0.4131 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| c.2068T>A | S690T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S690T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, FATHMM, and polyPhen‑2 HumVar, whereas a majority of tools (SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default) predict a pathogenic impact. Predictions that are inconclusive (FoldX, premPS, AlphaMissense‑Optimized) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as Benign. Overall, the balance of evidence leans toward pathogenicity, and this conclusion does not contradict the absence of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.055536 | Structured | 0.247926 | Uncertain | 0.944 | 0.253 | 0.000 | -11.380 | Likely Pathogenic | 0.845 | Likely Pathogenic | Ambiguous | 0.99 | Ambiguous | 0.2 | -0.21 | Likely Benign | 0.39 | Likely Benign | 0.67 | Ambiguous | 0.311 | Likely Benign | -2.84 | Deleterious | 0.943 | Possibly Damaging | 0.267 | Benign | 3.37 | Benign | 0.01 | Affected | 0.1059 | 0.4674 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.2095G>C | V699L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V699L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, premPS, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the preponderance of evidence, and this assessment does not contradict any ClinVar status, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.069024 | Structured | 0.432975 | Uncertain | 0.935 | 0.315 | 0.000 | -8.301 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | -0.58 | Ambiguous | 0.1 | -0.36 | Likely Benign | -0.47 | Likely Benign | 0.69 | Ambiguous | 0.150 | Likely Benign | -2.14 | Neutral | 0.448 | Benign | 0.153 | Benign | 3.48 | Benign | 0.10 | Tolerated | 0.0900 | 0.3289 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.2095G>T | V699L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V699L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Optimized. Only ESM1b predicts a pathogenic outcome, while FoldX, premPS, and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority; and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the consensus of the available tools, and this benign prediction does not contradict any ClinVar status, as no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.069024 | Structured | 0.432975 | Uncertain | 0.935 | 0.315 | 0.000 | -8.301 | Likely Pathogenic | 0.558 | Ambiguous | Likely Benign | -0.58 | Ambiguous | 0.1 | -0.36 | Likely Benign | -0.47 | Likely Benign | 0.69 | Ambiguous | 0.150 | Likely Benign | -2.14 | Neutral | 0.448 | Benign | 0.153 | Benign | 3.48 | Benign | 0.10 | Tolerated | 0.0900 | 0.3289 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.2111G>C | S704T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S704T is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Consensus from multiple in‑silico predictors shows a predominance of benign calls: REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus. Only polyPhen‑2 HumDiv predicts a pathogenic effect, while FoldX remains inconclusive. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts benign. Overall, the aggregate evidence indicates that S704T is most likely benign, which is consistent with its ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.096677 | Structured | 0.383620 | Uncertain | 0.928 | 0.363 | 0.000 | Uncertain | 1 | -4.930 | Likely Benign | 0.265 | Likely Benign | Likely Benign | 0.80 | Ambiguous | 0.0 | 0.15 | Likely Benign | 0.48 | Likely Benign | 0.29 | Likely Benign | 0.071 | Likely Benign | -1.72 | Neutral | 0.525 | Possibly Damaging | 0.107 | Benign | 3.45 | Benign | 0.07 | Tolerated | 3.47 | 10 | 0.1036 | 0.4674 | 1 | 1 | 0.1 | 14.03 | 201.7 | -18.0 | 0.0 | 0.0 | -0.2 | 0.7 | X | Potentially Benign | Ser704 is located at the end and outer surface of an α-helix (res. Thr704-Gly712), which is connected via a tight turn or loop to another α-helix (res. Asp684-Gln702). The hydroxyl side chain of Ser704 occasionally forms a hydrogen bond with the amide group of Ala707. Similarly, in the variant simulations, the hydroxyl side chain of Thr704 forms hydrogen bonds with the amide groups of Ala707 and Leu708. Thus, the residue swap does not cause any apparent structural change. | ||||||||||||||||
| c.2135G>C | G712A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 G712A 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, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from FoldX, Rosetta, Foldetta, PROVEAN, polyPhen‑2 (HumDiv and HumVar), and SIFT. Two tools report uncertainty: premPS and AlphaMissense‑Default. High‑accuracy assessments further refine the picture. 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 (2 benign vs. 1 pathogenic vote). Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, predicts a pathogenic effect. Because the majority of conventional predictors (7/11) indicate pathogenicity, the overall consensus leans toward a pathogenic impact, despite the mixed high‑accuracy results. 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. | GAP | 0.278302 | Structured | 0.384858 | Uncertain | 0.947 | 0.365 | 0.000 | -6.444 | Likely Benign | 0.553 | Ambiguous | Likely Benign | 2.89 | Destabilizing | 0.1 | 4.98 | Destabilizing | 3.94 | Destabilizing | 0.70 | Ambiguous | 0.281 | Likely Benign | -4.99 | Deleterious | 0.999 | Probably Damaging | 0.991 | Probably Damaging | 3.44 | Benign | 0.02 | Affected | 0.3993 | 0.4105 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.213C>A | D71E 2D AIThe SynGAP1 missense variant D71E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect, 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 | 0.575842 | Disordered | 0.456046 | Uncertain | 0.350 | 0.799 | 0.375 | -3.276 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -0.28 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.39 | Benign | 0.00 | Affected | 0.1490 | 0.5922 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.213C>G | D71E 2D AIThe SynGAP1 missense variant D71E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic call comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign; Foldetta results are not available. Overall, the consensus of the available predictions points to a benign impact, and this is consistent with the lack of ClinVar evidence or population data. 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 | 0.575842 | Disordered | 0.456046 | Uncertain | 0.350 | 0.799 | 0.375 | -3.276 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -0.28 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.39 | Benign | 0.00 | Affected | 0.1490 | 0.5922 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2160C>A | D720E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -5.527 | Likely Benign | 0.391 | Ambiguous | Likely Benign | -0.31 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.36 | Likely Benign | 0.23 | Likely Benign | 0.131 | Likely Benign | -2.46 | Neutral | 0.975 | Probably Damaging | 0.969 | Probably Damaging | 2.46 | Pathogenic | 0.15 | Tolerated | 0.1310 | 0.5275 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.2160C>G | D720E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D720E missense variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments reinforce the benign interpretation: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) yields a benign majority, and Foldetta also predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the variant is most likely benign based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.374039 | Structured | 0.450695 | Uncertain | 0.955 | 0.417 | 0.125 | -5.527 | Likely Benign | 0.391 | Ambiguous | Likely Benign | -0.31 | Likely Benign | 0.1 | -0.41 | Likely Benign | -0.36 | Likely Benign | 0.23 | Likely Benign | 0.131 | Likely Benign | -2.46 | Neutral | 0.975 | Probably Damaging | 0.969 | Probably Damaging | 2.46 | Pathogenic | 0.15 | Tolerated | 0.1310 | 0.5275 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.2165G>C | S722T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S722T is reported in gnomAD (6‑33441630‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, Rosetta, Foldetta, premPS, 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 FoldX is uncertain. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is benign; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, also predicts 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.468512 | Structured | 0.457186 | Uncertain | 0.950 | 0.431 | 0.375 | 6-33441630-G-C | 1 | 6.20e-7 | -5.734 | Likely Benign | 0.202 | Likely Benign | Likely Benign | 0.53 | Ambiguous | 0.0 | -0.32 | Likely Benign | 0.11 | Likely Benign | -0.12 | Likely Benign | 0.118 | Likely Benign | -0.57 | Neutral | 0.921 | Possibly Damaging | 0.414 | Benign | 2.57 | Benign | 1.00 | Tolerated | 3.50 | 8 | 0.1357 | 0.4363 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||
| c.2204G>C | S735T 2D AIThe SynGAP1 missense variant S735T 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, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. 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, 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 | 0.916840 | Disordered | 0.412174 | Uncertain | 0.290 | 0.752 | 0.875 | -5.340 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.03 | Neutral | 0.980 | Probably Damaging | 0.799 | Possibly Damaging | 2.67 | Benign | 0.46 | Tolerated | 0.1464 | 0.5321 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2213G>C | S738T 2D AIThe SynGAP1 missense variant S738T 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 score the variant 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) 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 consensus of all available predictions is that the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.441162 | Uncertain | 0.284 | 0.827 | 0.875 | -3.926 | Likely Benign | 0.062 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.68 | Neutral | 0.010 | Benign | 0.010 | Benign | 2.73 | Benign | 0.51 | Tolerated | 0.1336 | 0.4227 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.221G>C | S74T 2D AIThe SynGAP1 missense variant S74T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign prediction. Foldetta, a protein‑folding stability method, has no available result for this variant. 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 ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.505461 | Disordered | 0.450156 | Uncertain | 0.294 | 0.831 | 0.500 | -3.874 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.53 | Neutral | 0.000 | Benign | 0.000 | Benign | 4.22 | Benign | 0.00 | Affected | 0.1573 | 0.4704 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2236G>C | V746L 2D AIThe SynGAP1 missense variant V746L is catalogued in gnomAD (ID 6‑33441701‑G‑C) 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 is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | 6-33441701-G-C | 1 | 6.19e-7 | -3.260 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.015 | Likely Benign | -0.68 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.0896 | 0.5065 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2236G>T | V746L 2D AIThe SynGAP1 missense variant V746L 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 predict a benign effect. No tool in the dataset indicates pathogenicity. High‑accuracy assessments corroborate this benign prediction: AlphaMissense‑Optimized scores the variant as benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of all available predictions is that V746L 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 | 0.808535 | Disordered | 0.576597 | Binding | 0.336 | 0.867 | 0.875 | -3.260 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.015 | Likely Benign | -0.68 | Neutral | 0.002 | Benign | 0.003 | Benign | 2.82 | Benign | 0.08 | Tolerated | 4.32 | 2 | 0.0896 | 0.5065 | 1 | 2 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2239G>A | V747I 2D AIThe SynGAP1 missense variant V747I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.594069 | Binding | 0.343 | 0.873 | 0.750 | -3.981 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.08 | Neutral | 0.002 | Benign | 0.008 | Benign | 2.70 | Benign | 0.00 | Affected | 0.0560 | 0.3018 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2239G>C | V747L 2D AIThe SynGAP1 missense variant V747L (ClinVar ID 1985039.0) is listed as ClinVar status Uncertain and is present in gnomAD (6‑33441704‑G‑C). Prediction tools that agree on a benign effect include REVEL, 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). Only SIFT 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 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 | 0.816150 | Disordered | 0.594069 | Binding | 0.343 | 0.873 | 0.750 | Uncertain | 1 | 6-33441704-G-C | 2 | 1.24e-6 | -2.790 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.047 | Likely Benign | -0.52 | Neutral | 0.065 | Benign | 0.033 | Benign | 2.67 | Benign | 0.00 | Affected | 4.32 | 2 | 0.0699 | 0.3674 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2239G>T | V747L 2D AIThe SynGAP1 missense variant V747L is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign.” Only SIFT predicts a pathogenic outcome. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.816150 | Disordered | 0.594069 | Binding | 0.343 | 0.873 | 0.750 | -2.790 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.52 | Neutral | 0.065 | Benign | 0.033 | Benign | 2.67 | Benign | 0.00 | Affected | 4.32 | 2 | 0.0699 | 0.3674 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2249G>C | G750A 2D AIThe SynGAP1 missense variant G750A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.646832 | Binding | 0.348 | 0.866 | 0.625 | -3.263 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -1.65 | Neutral | 0.996 | Probably Damaging | 0.887 | Possibly Damaging | 2.52 | Benign | 0.04 | Affected | 0.3683 | 0.4792 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2254T>A | S752T 2D AIThe SynGAP1 missense variant S752T 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict 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. | Likely Benign | 0.604312 | Disordered | 0.690594 | Binding | 0.365 | 0.877 | 0.625 | -4.040 | Likely Benign | 0.101 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -1.33 | Neutral | 0.248 | Benign | 0.137 | Benign | 1.55 | Pathogenic | 0.07 | Tolerated | 0.1633 | 0.6342 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.226T>A | S76T 2D AIThe SynGAP1 missense variant S76T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, 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 | 0.517562 | Disordered | 0.444487 | Uncertain | 0.279 | 0.826 | 0.500 | -4.000 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.73 | Neutral | 0.805 | Possibly Damaging | 0.483 | Possibly Damaging | 3.78 | Benign | 0.00 | Affected | 0.1117 | 0.4774 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2270G>C | G757A 2D AIThe SynGAP1 missense change G757A is catalogued in ClinVar (ID 3635272.0) with an uncertain significance designation and is not reported in gnomAD. Functional prediction algorithms uniformly classify the variant 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 dataset predicts pathogenicity. High‑accuracy consensus methods corroborate this view: the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect, and AlphaMissense‑Optimized also predicts benign. The Foldetta stability assessment is unavailable for this variant. Taken together, the evidence overwhelmingly supports a benign interpretation, 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 | 0.436924 | Structured | 0.830995 | Binding | 0.310 | 0.869 | 0.375 | Uncertain | 1 | -2.626 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.066 | Likely Benign | -0.45 | Neutral | 0.267 | Benign | 0.127 | Benign | 2.73 | Benign | 0.35 | Tolerated | 0.3690 | 0.3842 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2286C>A | D762E 2D AIThe SynGAP1 D762E 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, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.332 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.144 | Likely Benign | -1.59 | Neutral | 0.994 | Probably Damaging | 0.891 | Possibly Damaging | 2.18 | Pathogenic | 0.05 | Affected | 0.1911 | 0.8236 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2286C>G | D762E 2D AIThe SynGAP1 D762E 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, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign, and Foldetta results are unavailable. Overall, the majority of high‑confidence predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.405110 | Structured | 0.910475 | Binding | 0.308 | 0.859 | 0.125 | -4.332 | Likely Benign | 0.459 | Ambiguous | Likely Benign | 0.144 | Likely Benign | -1.59 | Neutral | 0.994 | Probably Damaging | 0.891 | Possibly Damaging | 2.18 | Pathogenic | 0.05 | Affected | 0.1911 | 0.8236 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2294G>C | S765T 2D AIThe SynGAP1 missense variant S765T 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‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The predictions do not contradict 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 | 0.370445 | Structured | 0.922652 | Binding | 0.335 | 0.865 | 0.250 | -4.233 | Likely Benign | 0.215 | Likely Benign | Likely Benign | 0.094 | Likely Benign | -1.12 | Neutral | 0.963 | Probably Damaging | 0.950 | Probably Damaging | 4.13 | Benign | 0.37 | Tolerated | 0.1312 | 0.6673 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2296T>A | S766T 2D AIThe SynGAP1 missense variant S766T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.405110 | Structured | 0.923125 | Binding | 0.338 | 0.874 | 0.250 | -4.923 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -1.25 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 4.15 | Benign | 0.02 | Affected | 0.1461 | 0.6511 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2304C>A | D768E 2D AIThe SynGAP1 missense variant D768E is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools uniformly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and FATHMM all classify the change 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, reports a likely benign classification. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the computational evidence strongly supports a benign effect for D768E, 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 | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | -4.611 | Likely Benign | 0.380 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.23 | Neutral | 0.393 | Benign | 0.171 | Benign | 4.16 | Benign | 0.17 | Tolerated | 0.1368 | 0.7729 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2304C>G | D768E 2D AIThe SynGAP1 missense variant D768E 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. 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 computational evidence strongly suggests that D768E 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 | 0.332115 | Structured | 0.928237 | Binding | 0.314 | 0.877 | 0.250 | -4.611 | Likely Benign | 0.380 | Ambiguous | Likely Benign | 0.065 | Likely Benign | -1.23 | Neutral | 0.393 | Benign | 0.171 | Benign | 4.16 | Benign | 0.17 | Tolerated | 0.1368 | 0.7729 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.230G>C | S77T 2D AIThe SynGAP1 missense variant S77T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (majority vote) also indicates Likely Benign. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of computational evidence points to a benign effect, and this 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 | 0.490133 | Structured | 0.446124 | Uncertain | 0.310 | 0.855 | 0.375 | -4.204 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.03 | Neutral | 0.092 | Benign | 0.007 | Benign | 4.19 | Benign | 0.00 | Affected | 0.1180 | 0.5003 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2311T>A | S771T 2D AIThe SynGAP1 missense variant S771T 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 and the high‑accuracy predictions point to a benign impact. This conclusion is consistent with the lack of ClinVar evidence and does not contradict any existing database status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.436924 | Structured | 0.922503 | Binding | 0.306 | 0.883 | 0.250 | -4.765 | Likely Benign | 0.112 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -1.38 | Neutral | 0.649 | Possibly Damaging | 0.433 | Benign | 4.07 | Benign | 0.23 | Tolerated | 0.1497 | 0.6310 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2327G>C | G776A 2D AIThe SynGAP1 missense variant G776A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G776A, 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 | 0.377384 | Structured | 0.886983 | Binding | 0.296 | 0.888 | 0.250 | -5.275 | Likely Benign | 0.296 | Likely Benign | Likely Benign | 0.173 | Likely Benign | -1.82 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 4.26 | Benign | 0.03 | Affected | 0.3648 | 0.4971 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2336G>C | S779T 2D AIThe SynGAP1 missense variant S779T 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, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as tolerated or benign. Only two tools—polyPhen‑2 HumDiv and FATHMM—suggest a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates likely benign. Foldetta results are not available for this variant. Overall, the consensus of available predictions 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 | 0.509769 | Disordered | 0.834974 | Binding | 0.321 | 0.890 | 0.375 | -4.458 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -0.71 | Neutral | 0.611 | Possibly Damaging | 0.396 | Benign | 2.34 | Pathogenic | 0.79 | Tolerated | 0.1491 | 0.6392 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2338T>A | S780T 2D AIThe SynGAP1 missense variant S780T is reported in ClinVar as “Not submitted” and is not present in 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. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, SGM‑Consensus is likely benign, while 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 any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.812415 | Binding | 0.283 | 0.883 | 0.500 | -4.911 | Likely Benign | 0.157 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -0.63 | Neutral | 0.951 | Possibly Damaging | 0.614 | Possibly Damaging | 2.66 | Benign | 0.84 | Tolerated | 0.1445 | 0.6631 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2346C>A | D782E 2D AIThe SynGAP1 missense variant D782E is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign majority (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -4.447 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.75 | Neutral | 0.561 | Possibly Damaging | 0.207 | Benign | 2.14 | Pathogenic | 0.01 | Affected | 0.1351 | 0.7036 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2346C>G | D782E 2D AIThe SynGAP1 missense variant D782E is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a majority benign vote (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.604312 | Disordered | 0.768342 | Binding | 0.285 | 0.883 | 0.625 | -4.447 | Likely Benign | 0.486 | Ambiguous | Likely Benign | 0.127 | Likely Benign | -1.75 | Neutral | 0.561 | Possibly Damaging | 0.207 | Benign | 2.14 | Pathogenic | 0.01 | Affected | 0.1351 | 0.7036 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2362T>A | S788T 2D AIThe SynGAP1 missense variant S788T is listed in ClinVar with an uncertain significance (ClinVar ID 392728.0) and is present in the gnomAD database (gnomAD ID 6‑33442914‑T‑A). Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score, which is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN. Tools that predict a pathogenic outcome are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM‑Consensus (majority vote) also favors a benign interpretation. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to a benign effect, which is consistent with the ClinVar uncertain status rather than contradicting it. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.956248 | Disordered | 0.573557 | Binding | 0.349 | 0.895 | 0.750 | Uncertain | 2 | 6-33442914-T-A | 4 | 2.49e-6 | -4.288 | Likely Benign | 0.288 | Likely Benign | Likely Benign | 0.092 | Likely Benign | -2.25 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 1.55 | Pathogenic | 0.02 | Affected | 3.64 | 6 | 0.1794 | 0.6339 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||
| c.2399G>C | G800A 2D AIThe SynGAP1 missense variant G800A is listed in gnomAD (6-33442951‑G‑C) but has no ClinVar entry. Across the available in‑silico predictors, every tool reports a benign effect: SGM‑Consensus (Likely Benign), REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool predicts pathogenicity. High‑accuracy assessments reinforce this: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no reported result for this variant. Based on the unanimous benign predictions and the absence of any pathogenic calls, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.852992 | Disordered | 0.588350 | Binding | 0.303 | 0.884 | 0.625 | 6-33442951-G-C | 7 | 4.34e-6 | -3.550 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.031 | Likely Benign | -0.48 | Neutral | 0.011 | Benign | 0.006 | Benign | 2.78 | Benign | 1.00 | Tolerated | 4.32 | 2 | 0.3466 | 0.4850 | 0 | 1 | 2.2 | 14.03 | 10.1016/j.ajhg.2020.11.011 | ||||||||||||||||||||||||||||||||
| c.2402G>C | G801A 2D AIThe SynGAP1 missense variant G801A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). 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 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 not available, so they do not influence the assessment. **Overall, 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 | SH3-binding motif | 0.874069 | Disordered | 0.636323 | Binding | 0.320 | 0.892 | 0.625 | -3.747 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.025 | Likely Benign | -0.61 | Neutral | 0.025 | Benign | 0.034 | Benign | 2.83 | Benign | 0.50 | Tolerated | 0.3458 | 0.4681 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2405G>C | G802A 2D AIThe SynGAP1 missense variant G802A is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it to be pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign; Foldetta results are not available. Overall, the preponderance of evidence indicates that G802A 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 | SH3-binding motif | 0.894241 | Disordered | 0.681966 | Binding | 0.294 | 0.898 | 0.625 | -3.584 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.57 | Neutral | 0.059 | Benign | 0.089 | Benign | 2.74 | Benign | 0.02 | Affected | 0.3779 | 0.4554 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2412C>A | D804E 2D AIThe SynGAP1 D804E missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -4.155 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.035 | Likely Benign | -2.03 | Neutral | 0.400 | Benign | 0.138 | Benign | 1.26 | Pathogenic | 0.04 | Affected | 0.1765 | 0.6850 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2412C>G | D804E 2D AIThe SynGAP1 D804E missense variant is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which is a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” (3 benign vs. 1 pathogenic). High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus (majority vote) as benign, and Foldetta results are unavailable. Based on the overall consensus of the available predictions, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.801317 | Disordered | 0.786762 | Binding | 0.294 | 0.900 | 0.625 | -4.155 | Likely Benign | 0.243 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -2.03 | Neutral | 0.400 | Benign | 0.138 | Benign | 1.26 | Pathogenic | 0.04 | Affected | 0.1765 | 0.6850 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2422G>A | V808I 2D AIThe SynGAP1 missense variant V808I is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from polyPhen‑2 HumDiv, SIFT, and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign and the SGM‑Consensus (majority vote) is likely benign; Foldetta results are not available. Overall, the preponderance of evidence indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -4.190 | Likely Benign | 0.151 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.67 | Neutral | 0.659 | Possibly Damaging | 0.191 | Benign | 2.33 | Pathogenic | 0.00 | Affected | 0.0935 | 0.4282 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2422G>C | V808L 2D AIThe SynGAP1 missense variant V808L is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact for V808L, 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 | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.82 | Neutral | 0.911 | Possibly Damaging | 0.621 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1166 | 0.4745 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2422G>T | V808L 2D AIThe SynGAP1 missense variant V808L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | SH3-binding motif | 0.699094 | Disordered | 0.856438 | Binding | 0.289 | 0.903 | 0.500 | -4.723 | Likely Benign | 0.306 | Likely Benign | Likely Benign | 0.188 | Likely Benign | -1.82 | Neutral | 0.911 | Possibly Damaging | 0.621 | Possibly Damaging | 2.33 | Pathogenic | 0.00 | Affected | 0.1166 | 0.4745 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2426G>C | S809T 2D AIThe SynGAP1 missense variant S809T 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) also reports a likely benign outcome. Foldetta results are unavailable. 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 | SH3-binding motif | 0.626927 | Disordered | 0.853218 | Binding | 0.330 | 0.907 | 0.500 | -3.865 | Likely Benign | 0.091 | Likely Benign | Likely Benign | 0.076 | Likely Benign | 0.68 | Neutral | 0.003 | Benign | 0.010 | Benign | 2.95 | Benign | 0.82 | Tolerated | 0.1430 | 0.6617 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.2446T>A | S816T 2D AIThe SynGAP1 missense variant S816T 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 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 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 | 0.476583 | Structured | 0.747189 | Binding | 0.347 | 0.898 | 0.375 | -3.957 | Likely Benign | 0.408 | Ambiguous | Likely Benign | 0.064 | Likely Benign | -1.05 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.65 | Benign | 0.32 | Tolerated | 0.1573 | 0.5529 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2449T>A | S817T 2D AIThe SynGAP1 missense variant S817T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. AlphaMissense‑Default is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also leans benign, and Foldetta results are unavailable. Overall, the balance of evidence from both general and high‑accuracy predictors points to a benign impact for S817T. 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. | 0.490133 | Structured | 0.727082 | Binding | 0.314 | 0.901 | 0.625 | -6.544 | Likely Benign | 0.492 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -1.95 | Neutral | 0.990 | Probably Damaging | 0.846 | Possibly Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.1622 | 0.6482 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2468G>C | S823T 2D AIThe SynGAP1 missense variant S823T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized predicts benign, while Foldetta (combining FoldX‑MD and Rosetta) has no available result for this variant. Overall, the majority of standard predictors indicate a pathogenic effect, and this assessment does not contradict the lack of ClinVar annotation. Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.685117 | Disordered | 0.627336 | Binding | 0.358 | 0.884 | 0.750 | -6.036 | Likely Benign | 0.717 | Likely Pathogenic | Likely Benign | 0.165 | Likely Benign | -2.02 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 0.1453 | 0.6580 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2471G>C | S824T 2D AIThe SynGAP1 missense variant S824T 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 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 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 | 0.728858 | Disordered | 0.611272 | Binding | 0.314 | 0.884 | 0.750 | -4.135 | Likely Benign | 0.500 | Ambiguous | Likely Benign | 0.116 | Likely Benign | -0.74 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.62 | Benign | 0.47 | Tolerated | 0.1760 | 0.6525 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2473T>A | S825T 2D AIThe SynGAP1 missense variant S825T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN is inconclusive (two benign, two pathogenic). AlphaMissense‑Optimized, a high‑accuracy model, predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of standard tools (5 pathogenic vs. 4 benign) suggest a pathogenic impact, while the single high‑accuracy model indicates benign. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.675549 | Disordered | 0.618614 | Binding | 0.384 | 0.886 | 0.750 | -4.659 | Likely Benign | 0.615 | Likely Pathogenic | Likely Benign | 0.155 | Likely Benign | -2.26 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.07 | Pathogenic | 0.05 | Affected | 0.1432 | 0.6658 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2478C>A | D826E 2D AIThe SynGAP1 missense variant D826E 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, 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 because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -4.172 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -0.66 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.92 | Benign | 0.56 | Tolerated | 0.1795 | 0.7687 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2478C>G | D826E 2D AIThe SynGAP1 missense variant D826E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. 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 | 0.666105 | Disordered | 0.627309 | Binding | 0.327 | 0.886 | 0.625 | -4.172 | Likely Benign | 0.859 | Likely Pathogenic | Ambiguous | 0.164 | Likely Benign | -0.66 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.92 | Benign | 0.56 | Tolerated | 0.1795 | 0.7687 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2507G>C | S836T 2D AIThe SynGAP1 missense variant S836T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates the majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.634582 | Binding | 0.269 | 0.859 | 0.250 | -3.871 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -1.28 | Neutral | 0.901 | Possibly Damaging | 0.535 | Possibly Damaging | 2.56 | Benign | 0.36 | Tolerated | 0.1161 | 0.5326 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2509G>A | V837I 2D AIThe SynGAP1 missense variant V837I is reported in ClinVar as “Not submitted” and is present in gnomAD (variant ID 6-33443061‑G‑A). 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. When predictions are grouped by consensus, the benign group contains seven tools, while the pathogenic group contains two. High‑accuracy assessments reinforce the benign view: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely benign. Foldetta results are unavailable. Overall, the majority of evidence indicates that V837I is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | 6-33443061-G-A | 1 | 6.19e-7 | -4.299 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.119 | Likely Benign | -0.51 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.13 | Tolerated | 3.77 | 5 | 0.0833 | 0.3848 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2509G>C | V837L 2D AIThe SynGAP1 missense variant V837L 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‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.626284 | Binding | 0.318 | 0.871 | 0.125 | -4.895 | Likely Benign | 0.313 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.15 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.64 | Benign | 0.17 | Tolerated | 0.1039 | 0.4623 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2519G>C | S840T 2D AIThe SynGAP1 missense variant S840T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, and AlphaMissense‑Default; ESM1b remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is pathogenic. Foldetta results are unavailable. Overall, the majority of predictions (five pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.611356 | Binding | 0.259 | 0.865 | 0.250 | -7.243 | In-Between | 0.583 | Likely Pathogenic | Likely Benign | 0.170 | Likely Benign | -2.30 | Neutral | 0.951 | Possibly Damaging | 0.729 | Possibly Damaging | 1.55 | Pathogenic | 0.00 | Affected | 0.1068 | 0.5494 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2521G>C | V841L 2D AIThe SynGAP1 missense variant V841L is not 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—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 results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | -7.924 | In-Between | 0.514 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -0.01 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.85 | Benign | 0.56 | Tolerated | 0.0850 | 0.4233 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2521G>T | V841L 2D AIThe SynGAP1 missense variant V841L is not 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—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 results 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. | 0.622677 | Disordered | 0.616495 | Binding | 0.261 | 0.873 | 0.125 | -7.924 | In-Between | 0.514 | Ambiguous | Likely Benign | 0.157 | Likely Benign | -0.01 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.85 | Benign | 0.56 | Tolerated | 0.0850 | 0.4233 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2524T>A | S842T 2D AIThe SynGAP1 missense variant S842T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Benign, while the SGM‑Consensus (majority of the four high‑accuracy predictors) is Pathogenic; Foldetta results are unavailable. Overall, the majority of evidence points to a pathogenic impact for S842T, and this conclusion does not contradict any ClinVar annotation because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.604312 | Disordered | 0.617281 | Binding | 0.274 | 0.861 | 0.250 | -13.443 | Likely Pathogenic | 0.725 | Likely Pathogenic | Likely Benign | 0.163 | Likely Benign | -2.23 | Neutral | 0.983 | Probably Damaging | 0.702 | Possibly Damaging | 2.15 | Pathogenic | 0.00 | Affected | 0.0974 | 0.5391 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2535C>A | D845E 2D AIThe SynGAP1 missense variant D845E is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas seven tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus) predict a pathogenic outcome. The high‑accuracy AlphaMissense‑Optimized score is uncertain, and Foldetta stability analysis is unavailable. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Pathogenic. Overall, the balance of evidence points to a pathogenic effect for D845E, 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 | 0.553315 | Disordered | 0.599971 | Binding | 0.297 | 0.827 | 0.500 | -6.979 | Likely Benign | 0.914 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -2.67 | Deleterious | 0.992 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1404 | 0.6998 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2535C>G | D845E 2D AIThe SynGAP1 missense variant D845E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized is uncertain, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—classifies the variant as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence points to a pathogenic effect for D845E, and this conclusion does not contradict any existing ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.553315 | Disordered | 0.599971 | Binding | 0.297 | 0.827 | 0.500 | -6.979 | Likely Benign | 0.914 | Likely Pathogenic | Ambiguous | 0.196 | Likely Benign | -2.67 | Deleterious | 0.992 | Probably Damaging | 0.992 | Probably Damaging | 2.02 | Pathogenic | 0.00 | Affected | 0.1404 | 0.6998 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2543G>C | G848A 2D AIThe SynGAP1 missense variant G848A 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Based on the preponderance of evidence, 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 | 0.724957 | Disordered | 0.563942 | Binding | 0.287 | 0.816 | 0.500 | -3.560 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.115 | Likely Benign | -0.48 | Neutral | 0.856 | Possibly Damaging | 0.554 | Possibly Damaging | 2.61 | Benign | 0.07 | Tolerated | 0.3971 | 0.5145 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2547T>A | D849E 2D AIThe SynGAP1 missense variant D849E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” consensus. 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, was not available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.554191 | Binding | 0.319 | 0.813 | 0.500 | -2.911 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -0.55 | Neutral | 0.393 | Benign | 0.187 | Benign | 4.25 | Benign | 0.00 | Affected | 0.1955 | 0.7819 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2547T>G | D849E 2D AIThe SynGAP1 missense variant D849E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. 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 benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.712013 | Disordered | 0.554191 | Binding | 0.319 | 0.813 | 0.500 | -2.911 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.087 | Likely Benign | -0.55 | Neutral | 0.393 | Benign | 0.187 | Benign | 4.25 | Benign | 0.00 | Affected | 0.1955 | 0.7819 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2549G>C | G850A 2D AIThe SynGAP1 missense variant G850A 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 Likely Benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign impact, 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 | 0.648219 | Disordered | 0.540897 | Binding | 0.312 | 0.820 | 0.500 | -4.731 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.60 | Neutral | 0.580 | Possibly Damaging | 0.303 | Benign | 4.27 | Benign | 0.09 | Tolerated | 0.3991 | 0.4837 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2555G>C | G852A 2D AIThe SynGAP1 missense variant G852A 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. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.733139 | Disordered | 0.506063 | Binding | 0.276 | 0.816 | 0.625 | -4.493 | Likely Benign | 0.068 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -0.35 | Neutral | 0.393 | Benign | 0.321 | Benign | 4.25 | Benign | 1.00 | Tolerated | 0.3895 | 0.4934 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2558G>C | G853A 2D AIThe SynGAP1 missense variant G853A is predicted to be benign by every evaluated in‑silico tool. Benign predictions come from 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 view: AlphaMissense‑Optimized reports a benign effect, and the SGM Consensus (a 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. ClinVar contains no entry for G853A, and the variant is absent from gnomAD. Based on the unanimous benign predictions and lack of contrary evidence, the variant is most likely benign, with no contradiction from ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.496246 | Uncertain | 0.284 | 0.815 | 0.625 | -4.440 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.165 | Likely Benign | -0.30 | Neutral | 0.124 | Benign | 0.130 | Benign | 4.20 | Benign | 0.30 | Tolerated | 0.3929 | 0.5527 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.256G>A | V86I 2D AIThe SynGAP1 missense variant V86I is listed in ClinVar (ID 588267.0) with an “Uncertain” status and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the variant as benign or likely benign. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is “Likely Benign.” No Foldetta (FoldX‑MD/Rosetta stability) result is available, so it does not influence the assessment. Overall, the majority of predictions indicate that V86I is most likely benign, 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 | 0.685117 | Disordered | 0.552911 | Binding | 0.295 | 0.887 | 0.500 | Uncertain | 1 | -4.726 | Likely Benign | 0.338 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.31 | Neutral | 0.267 | Benign | 0.097 | Benign | 3.94 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0887 | 0.4417 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||
| c.256G>C | V86L 2D AIThe SynGAP1 missense variant V86L is reported in ClinVar as “not listed” and is present in the gnomAD database (ID 6‑33425864‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, and FATHMM. Tools that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as likely benign. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, while the SGM‑Consensus remains benign; Foldetta stability analysis is unavailable. Overall, the balance of evidence favors a benign interpretation, 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. | Likely Benign | 0.685117 | Disordered | 0.552911 | Binding | 0.295 | 0.887 | 0.500 | 6-33425864-G-C | 1 | 6.20e-7 | -3.658 | Likely Benign | 0.965 | Likely Pathogenic | Likely Pathogenic | 0.081 | Likely Benign | -0.84 | Neutral | 0.267 | Benign | 0.097 | Benign | 3.85 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1121 | 0.5386 | 1 | 2 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2570G>C | S857T 2D AIThe SynGAP1 missense variant S857T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also 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 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 | 0.728858 | Disordered | 0.475747 | Uncertain | 0.288 | 0.826 | 0.375 | -4.840 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -0.31 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 4.09 | Benign | 0.33 | Tolerated | 0.1645 | 0.6733 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2573G>C | S858T 2D AIThe SynGAP1 missense variant S858T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only polyPhen‑2 HumVar predicts it as pathogenic, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Benign. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the consensus of the majority of prediction tools and the high‑accuracy methods indicates that S858T is most likely benign, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.724957 | Disordered | 0.482724 | Uncertain | 0.305 | 0.833 | 0.375 | -4.960 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.92 | Neutral | 0.259 | Benign | 0.786 | Possibly Damaging | 4.14 | Benign | 0.06 | Tolerated | 0.1660 | 0.6489 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2576G>C | S859T 2D AIThe SynGAP1 missense variant S859T 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. ESM1b is uncertain. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.648219 | Disordered | 0.497075 | Uncertain | 0.288 | 0.819 | 0.375 | -7.155 | In-Between | 0.089 | Likely Benign | Likely Benign | 0.154 | Likely Benign | -0.97 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 4.02 | Benign | 0.24 | Tolerated | 0.1345 | 0.6434 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2578G>A | V860I 2D AIThe SynGAP1 missense variant V860I is listed in ClinVar (ID 411591) as Benign and is present in the gnomAD database (6‑33443130‑G‑A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized reports Benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Benign, while a Foldetta stability analysis is unavailable. Overall, the majority of computational evidence points to a benign impact, which is consistent with the ClinVar designation and does not contradict the reported clinical status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.518121 | Binding | 0.269 | 0.803 | 0.250 | Benign/Likely benign | 2 | 6-33443130-G-A | 21 | 1.30e-5 | -4.516 | Likely Benign | 0.095 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -0.42 | Neutral | 0.009 | Benign | 0.006 | Benign | 4.24 | Benign | 0.00 | Affected | 3.77 | 5 | 0.0842 | 0.4477 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2578G>C | V860L 2D AIThe SynGAP1 missense variant V860L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus also indicates a benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.545602 | Disordered | 0.518121 | Binding | 0.269 | 0.803 | 0.250 | -3.053 | Likely Benign | 0.123 | Likely Benign | Likely Benign | 0.028 | Likely Benign | -0.89 | Neutral | 0.124 | Benign | 0.037 | Benign | 4.17 | Benign | 0.00 | Affected | 0.1052 | 0.5446 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2581T>A | S861T 2D AIThe SynGAP1 missense variant S861T 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. The high‑accuracy consensus, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN), also reports a likely benign outcome. AlphaMissense‑Optimized likewise predicts benign. 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 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 | 0.557691 | Disordered | 0.540903 | Binding | 0.285 | 0.797 | 0.250 | -4.462 | Likely Benign | 0.096 | Likely Benign | Likely Benign | 0.022 | Likely Benign | -0.83 | Neutral | 0.043 | Benign | 0.026 | Benign | 3.99 | Benign | 0.14 | Tolerated | 0.1262 | 0.6245 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2596G>A | V866I 2D AIThe SynGAP1 missense variant V866I is listed in ClinVar with an “Uncertain” status (ClinVar ID 536995.0) and is present in gnomAD (6‑33443148‑G‑A). 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 and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | Conflicting | 3 | 6-33443148-G-A | 5 | 3.10e-6 | -4.652 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -0.39 | Neutral | 0.957 | Probably Damaging | 0.541 | Possibly Damaging | 2.69 | Benign | 0.27 | Tolerated | 3.82 | 4 | 0.0699 | 0.4004 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2596G>C | V866L 2D AIThe SynGAP1 missense variant V866L 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 | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | -3.352 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.97 | Neutral | 0.217 | Benign | 0.229 | Benign | 2.71 | Benign | 0.21 | Tolerated | 3.82 | 4 | 0.0836 | 0.4660 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2596G>T | V866L 2D AIThe SynGAP1 missense variant V866L is listed in ClinVar (ID 469150.0) with an “Uncertain” clinical significance and is present in gnomAD (6‑33443148‑G‑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 outcome. 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, did not provide a result for this variant. Overall, the computational evidence strongly supports a benign effect, and this conclusion does not contradict the current ClinVar status of uncertainty. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.638070 | Binding | 0.266 | 0.788 | 0.250 | Uncertain | 1 | 6-33443148-G-T | 1 | 6.20e-7 | -3.352 | Likely Benign | 0.148 | Likely Benign | Likely Benign | 0.046 | Likely Benign | -0.97 | Neutral | 0.217 | Benign | 0.229 | Benign | 2.71 | Benign | 0.21 | Tolerated | 3.82 | 4 | 0.0836 | 0.4660 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||
| c.259T>A | S87T 2D AIThe SynGAP1 missense variant S87T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is classified as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (majority vote) also indicates benign. No Foldetta stability prediction is available for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar status, as none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.550904 | Binding | 0.302 | 0.878 | 0.500 | -6.706 | Likely Benign | 0.776 | Likely Pathogenic | Likely Benign | 0.032 | Likely Benign | -1.23 | Neutral | 0.140 | Benign | 0.153 | Benign | 3.80 | Benign | 0.00 | Affected | 0.1001 | 0.4708 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2600G>C | G867A 2D AIThe SynGAP1 missense variant G867A 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‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.517562 | Disordered | 0.657954 | Binding | 0.285 | 0.801 | 0.250 | -4.638 | Likely Benign | 0.172 | Likely Benign | Likely Benign | 0.081 | Likely Benign | -1.18 | Neutral | 0.990 | Probably Damaging | 0.828 | Possibly Damaging | 2.79 | Benign | 0.94 | Tolerated | 0.3666 | 0.5534 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2604C>A | D868E 2D AIThe SynGAP1 missense variant D868E 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, PROVEAN) also indicates a likely benign outcome. In contrast, the two polyPhen‑2 implementations (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; no Foldetta stability data are available. Overall, the majority of evidence points to a benign impact, and this is consistent with the absence of a ClinVar pathogenic claim. Thus, the variant is most likely benign, and there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.792 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.47 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 2.68 | Benign | 0.36 | Tolerated | 0.2092 | 0.6392 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2604C>G | D868E 2D AIThe SynGAP1 missense variant D868E 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 two tools, polyPhen‑2 HumDiv and HumVar, predict pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.525368 | Disordered | 0.676362 | Binding | 0.262 | 0.815 | 0.250 | -3.792 | Likely Benign | 0.270 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.47 | Neutral | 0.966 | Probably Damaging | 0.848 | Possibly Damaging | 2.68 | Benign | 0.36 | Tolerated | 0.2092 | 0.6392 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2614T>A | S872T 2D AIThe SynGAP1 missense variant S872T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 for S872T, 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 | 0.486429 | Structured | 0.662664 | Binding | 0.262 | 0.865 | 0.125 | -5.129 | Likely Benign | 0.189 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -1.20 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.65 | Benign | 0.17 | Tolerated | 0.1738 | 0.6234 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2618G>C | S873T 2D AIThe SynGAP1 missense variant S873T 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‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. 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 also indicates Likely Benign. Foldetta results are not available for this variant. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.414856 | Structured | 0.649816 | Binding | 0.283 | 0.866 | 0.125 | -6.364 | Likely Benign | 0.301 | Likely Benign | Likely Benign | 0.152 | Likely Benign | -1.77 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.11 | Tolerated | 0.1514 | 0.6288 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2626T>A | S876T 2D AIThe SynGAP1 missense variant S876T 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‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the preponderance of evidence, 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 | 0.549308 | Disordered | 0.631130 | Binding | 0.280 | 0.872 | 0.250 | -5.158 | Likely Benign | 0.183 | Likely Benign | Likely Benign | 0.121 | Likely Benign | -1.91 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.60 | Benign | 0.11 | Tolerated | 0.1380 | 0.6790 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.262G>C | V88L 2D AIThe SynGAP1 V88L variant has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM. Those that predict a pathogenic effect are SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome; Foldetta results are unavailable. Overall, the majority of tools suggest a benign impact, but the high‑accuracy predictions are conflicting. The variant is most likely benign based on the collective evidence, and this assessment does not contradict any ClinVar status because no ClinVar classification exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.703578 | Disordered | 0.552910 | Binding | 0.323 | 0.870 | 0.500 | -5.808 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.066 | Likely Benign | -0.79 | Neutral | 0.225 | Benign | 0.027 | Benign | 3.74 | Benign | 0.00 | Affected | 0.1457 | 0.4562 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.262G>T | V88L 2D AIThe SynGAP1 missense variant V88L is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and FATHMM, whereas SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized predict a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as pathogenic, while the SGM Consensus (a majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign effect; a Foldetta stability analysis is unavailable. Overall, the majority of predictions lean toward a benign impact, and there is no ClinVar annotation to contradict this assessment. 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. | Likely Benign | 0.703578 | Disordered | 0.552910 | Binding | 0.323 | 0.870 | 0.500 | -5.808 | Likely Benign | 0.975 | Likely Pathogenic | Likely Pathogenic | 0.066 | Likely Benign | -0.79 | Neutral | 0.225 | Benign | 0.027 | Benign | 3.74 | Benign | 0.00 | Affected | 0.1457 | 0.4562 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2645G>C | G882A 2D AIThe SynGAP1 missense variant G882A 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 predict benign, whereas only FATHMM predicts pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign classification. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are unavailable. Overall, the majority of evidence indicates the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.632888 | Binding | 0.306 | 0.878 | 0.250 | -3.876 | Likely Benign | 0.131 | Likely Benign | Likely Benign | 0.048 | Likely Benign | -1.05 | Neutral | 0.004 | Benign | 0.002 | Benign | 2.14 | Pathogenic | 0.79 | Tolerated | 0.3345 | 0.5268 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2666G>C | G889A 2D AIThe SynGAP1 missense variant G889A is listed in gnomAD (6‑33443218‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, PolyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign or likely benign. Only FATHMM predicts a pathogenic outcome, representing a single dissenting signal. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized reports a benign effect, and the SGM‑Consensus likewise indicates a likely benign status. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, was not available for this variant. Overall, the preponderance of evidence supports a benign classification, and this conclusion does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.552581 | Binding | 0.331 | 0.928 | 0.625 | 6-33443218-G-C | 1 | 6.20e-7 | -4.580 | Likely Benign | 0.099 | Likely Benign | Likely Benign | 0.063 | Likely Benign | -1.49 | Neutral | 0.245 | Benign | 0.096 | Benign | 2.47 | Pathogenic | 0.76 | Tolerated | 4.32 | 4 | 0.3838 | 0.4902 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2674T>A | S892T 2D AIThe SynGAP1 missense variant S892T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.754692 | Disordered | 0.473390 | Uncertain | 0.319 | 0.926 | 0.875 | -4.806 | Likely Benign | 0.210 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.09 | Neutral | 0.975 | Probably Damaging | 0.748 | Possibly Damaging | 2.61 | Benign | 0.03 | Affected | 0.1606 | 0.5857 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2681G>C | G894A 2D AIThe SynGAP1 missense variant G894A is reported in gnomAD (ID 6‑33443233‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the SGM‑Consensus (majority vote from 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 unavailable. Overall, the preponderance of evidence indicates the variant is most likely benign, 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 | 0.788093 | Disordered | 0.425700 | Uncertain | 0.310 | 0.925 | 0.750 | 6-33443233-G-C | 1 | 6.20e-7 | -3.997 | Likely Benign | 0.267 | Likely Benign | Likely Benign | 0.180 | Likely Benign | -1.26 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.69 | Benign | 0.97 | Tolerated | 4.32 | 4 | 0.3857 | 0.4670 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2684G>C | S895T 2D AIThe SynGAP1 missense variant S895T is reported in gnomAD (variant ID 6-33443236‑G‑C) 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is benign, and AlphaMissense‑Optimized also scores benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The variant is most likely benign based on current predictions, 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 | 0.788093 | Disordered | 0.414977 | Uncertain | 0.294 | 0.925 | 0.750 | 6-33443236-G-C | 1 | 6.20e-7 | -5.515 | Likely Benign | 0.199 | Likely Benign | Likely Benign | 0.132 | Likely Benign | -1.14 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.75 | Benign | 0.26 | Tolerated | 4.32 | 4 | 0.1405 | 0.6392 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2687G>C | G896A 2D AIThe SynGAP1 missense variant G896A 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. 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 show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and there is no conflict with ClinVar status because no ClinVar claim exists. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.675549 | Disordered | 0.412816 | Uncertain | 0.314 | 0.923 | 0.625 | -3.562 | Likely Benign | 0.147 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.95 | Neutral | 0.561 | Possibly Damaging | 0.139 | Benign | 2.54 | Benign | 0.79 | Tolerated | 0.3799 | 0.4963 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2689T>A | S897T 2D AIThe SynGAP1 missense variant S897T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability prediction is available for this variant. Overall, the majority of computational evidence points to 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 | 0.699094 | Disordered | 0.418474 | Uncertain | 0.292 | 0.928 | 0.500 | -4.930 | Likely Benign | 0.145 | Likely Benign | Likely Benign | 0.086 | Likely Benign | -0.69 | Neutral | 0.790 | Possibly Damaging | 0.535 | Possibly Damaging | 2.68 | Benign | 0.04 | Affected | 0.1480 | 0.6392 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.268G>C | V90L 2D AIThe SynGAP1 missense variant V90L is not reported in ClinVar and has no entries 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), ESM1b, FATHMM, and AlphaMissense‑Optimized all classify the change as benign, while SIFT uniquely predicts it as pathogenic. The consensus from the SGM framework, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a Likely Benign verdict. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized reports a benign outcome, the SGM Consensus also indicates Likely Benign, and Foldetta data are unavailable. With the majority of evidence pointing to a benign effect and no conflicting ClinVar annotation, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.570702 | Disordered | 0.542047 | Binding | 0.343 | 0.873 | 0.500 | -3.676 | Likely Benign | 0.522 | Ambiguous | Likely Benign | 0.056 | Likely Benign | -0.24 | Neutral | 0.103 | Benign | 0.015 | Benign | 4.02 | Benign | 0.00 | Affected | 0.1334 | 0.4487 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.268G>T | V90L 2D AIThe SynGAP1 missense variant V90L is not reported in ClinVar and has no entries 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), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for V90L, 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 | 0.570702 | Disordered | 0.542047 | Binding | 0.343 | 0.873 | 0.500 | -3.676 | Likely Benign | 0.522 | Ambiguous | Likely Benign | 0.056 | Likely Benign | -0.24 | Neutral | 0.103 | Benign | 0.015 | Benign | 4.02 | Benign | 0.00 | Affected | 0.1334 | 0.4487 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2692T>A | S898T 2D AIThe SynGAP1 missense variant S898T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.690604 | Disordered | 0.426070 | Uncertain | 0.305 | 0.922 | 0.500 | -4.910 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.097 | Likely Benign | -0.33 | Neutral | 0.992 | Probably Damaging | 0.814 | Possibly Damaging | 2.50 | Benign | 0.78 | Tolerated | 0.1833 | 0.6209 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2708G>C | G903A 2D AIThe SynGAP1 missense variant G903A 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also as benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact for G903A. This conclusion is not contradicted by ClinVar, which has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.680603 | Disordered | 0.549818 | Binding | 0.291 | 0.917 | 0.375 | -2.843 | Likely Benign | 0.227 | Likely Benign | Likely Benign | 0.141 | Likely Benign | -1.54 | Neutral | 0.989 | Probably Damaging | 0.829 | Possibly Damaging | 2.43 | Pathogenic | 0.08 | Tolerated | 0.3490 | 0.5025 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2720G>C | S907T 2D AIThe SynGAP1 missense variant S907T 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‑Default, and AlphaMissense‑Optimized. The only tools that predict a pathogenic outcome are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. 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 | 0.637480 | Disordered | 0.661854 | Binding | 0.336 | 0.920 | 0.250 | -4.794 | Likely Benign | 0.220 | Likely Benign | Likely Benign | 0.178 | Likely Benign | -0.53 | Neutral | 0.992 | Probably Damaging | 0.846 | Possibly Damaging | 2.66 | Benign | 0.93 | Tolerated | 0.1324 | 0.6352 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2729G>C | G910A 2D AIThe SynGAP1 missense variant G910A is listed in ClinVar with an “Uncertain” status (ClinVar ID 2091237.0) and is present in gnomAD (6‑33443281‑G‑C). 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. The remaining predictions are uncertain: AlphaMissense‑Default is inconclusive, while the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign, SGM‑Consensus as likely benign, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, which does not contradict the ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.762850 | Disordered | 0.707319 | Binding | 0.264 | 0.917 | 0.250 | Uncertain | 1 | 6-33443281-G-C | 1 | 6.20e-7 | -3.587 | Likely Benign | 0.361 | Ambiguous | Likely Benign | 0.209 | Likely Benign | -1.43 | Neutral | 0.999 | Probably Damaging | 0.999 | Probably Damaging | 2.78 | Benign | 0.10 | Tolerated | 3.77 | 5 | 0.3753 | 0.4544 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2731G>A | V911I 2D AIThe SynGAP1 missense variant V911I 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, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “Likely Benign,” while 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 (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -3.983 | Likely Benign | 0.085 | Likely Benign | Likely Benign | 0.024 | Likely Benign | -0.32 | Neutral | 0.451 | Benign | 0.209 | Benign | 2.70 | Benign | 0.22 | Tolerated | 0.0881 | 0.4331 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2731G>C | V911L 2D AIThe SynGAP1 missense variant V911L is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity all converge on a benign outcome: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. No tool in the dataset indicates a pathogenic effect. 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) is classified as 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 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 | 0.685117 | Disordered | 0.724137 | Binding | 0.327 | 0.914 | 0.375 | -2.722 | Likely Benign | 0.166 | Likely Benign | Likely Benign | 0.100 | Likely Benign | -0.39 | Neutral | 0.451 | Benign | 0.157 | Benign | 2.73 | Benign | 0.16 | Tolerated | 0.1067 | 0.5310 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2742C>A | D914E 2D AIThe SynGAP1 missense variant D914E is reported in gnomAD (ID 6‑33443294‑C‑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, creating a single discordant call. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a “Likely Benign” classification, and AlphaMissense‑Optimized independently predicts benign. 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 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | 6-33443294-C-A | 5 | 3.10e-6 | -3.231 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.29 | Neutral | 0.893 | Possibly Damaging | 0.418 | Benign | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1909 | 0.7088 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2742C>G | D914E 2D AIThe SynGAP1 missense variant D914E 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 for D914E, 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 | 0.699094 | Disordered | 0.785987 | Binding | 0.320 | 0.892 | 0.250 | -3.231 | Likely Benign | 0.170 | Likely Benign | Likely Benign | 0.133 | Likely Benign | -0.29 | Neutral | 0.893 | Possibly Damaging | 0.418 | Benign | 2.87 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.1909 | 0.7088 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2744G>C | G915A 2D AIThe SynGAP1 missense variant G915A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns Benign, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available. Overall, the majority of evidence points to a benign effect for G915A, and this conclusion is not contradicted by any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.808641 | Binding | 0.302 | 0.880 | 0.375 | -4.007 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -1.22 | Neutral | 0.900 | Possibly Damaging | 0.622 | Possibly Damaging | 2.87 | Benign | 0.05 | Affected | 0.3454 | 0.4930 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2746G>A | V916I 2D AIThe SynGAP1 missense variant V916I is reported in gnomAD (variant ID 6-33443298‑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 indicate a benign effect. 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) reports a likely benign outcome. Foldetta, a protein‑folding stability predictor, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment 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 | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | 6-33443298-G-A | 25 | 1.55e-5 | -4.336 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -0.05 | Neutral | 0.010 | Benign | 0.015 | Benign | 2.71 | Benign | 0.09 | Tolerated | 3.77 | 5 | 0.0905 | 0.4463 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2746G>C | V916L 2D AIThe SynGAP1 missense variant V916L 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 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 | 0.642678 | Disordered | 0.835395 | Binding | 0.308 | 0.879 | 0.250 | -2.645 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.064 | Likely Benign | 0.31 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.73 | Benign | 0.09 | Tolerated | 0.1190 | 0.5323 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.275G>C | G92A 2D AIThe SynGAP1 missense variant G92A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (which is “Likely Benign”). In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized returns “Benign” and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates “Likely Benign.” No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G92A, 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 | 0.575842 | Disordered | 0.537848 | Binding | 0.337 | 0.874 | 0.625 | -4.044 | Likely Benign | 0.219 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -1.53 | Neutral | 0.996 | Probably Damaging | 0.910 | Probably Damaging | 4.08 | Benign | 0.00 | Affected | 0.3922 | 0.4930 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2776T>A | S926T 2D AIThe SynGAP1 missense variant S926T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized; pathogenic predictions come from polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus (SGM Consensus) is inconclusive, with two pathogenic and two benign votes. AlphaMissense‑Optimized, a high‑accuracy model, predicts benign, while Foldetta stability analysis is unavailable. Overall, the majority of standard tools favor a pathogenic effect, whereas the single high‑accuracy model suggests benign. Thus, the variant is most likely pathogenic based on the collective predictions, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.461924 | Structured | 0.981753 | Binding | 0.295 | 0.854 | 0.250 | -2.917 | Likely Benign | 0.651 | Likely Pathogenic | Likely Benign | 0.226 | Likely Benign | -2.34 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 1.55 | Pathogenic | 0.00 | Affected | 0.1174 | 0.5663 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2811T>A | D937E 2D AIThe SynGAP1 missense variant D937E 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 the two polyPhen‑2 implementations (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 assessments further support a benign interpretation: AlphaMissense‑Optimized is benign and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the consensus of the majority of prediction 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 | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -3.342 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.07 | Neutral | 0.990 | Probably Damaging | 0.801 | Possibly Damaging | 2.76 | Benign | 0.15 | Tolerated | 0.2524 | 0.6915 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2811T>G | D937E 2D AIThe SynGAP1 D937E 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, 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, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Based on the preponderance of benign predictions and the consensus from high‑accuracy methods, 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 | 0.819762 | Disordered | 0.963385 | Binding | 0.348 | 0.883 | 0.625 | -3.342 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.07 | Neutral | 0.990 | Probably Damaging | 0.801 | Possibly Damaging | 2.76 | Benign | 0.15 | Tolerated | 0.2524 | 0.6915 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2813G>C | G938A 2D AIThe SynGAP1 missense variant G938A 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‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. 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 a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus also indicates Likely Benign. Foldetta’s protein‑folding stability analysis is not available for this variant. Overall, the majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.905695 | Disordered | 0.949795 | Binding | 0.318 | 0.883 | 0.625 | -5.068 | Likely Benign | 0.139 | Likely Benign | Likely Benign | 0.095 | Likely Benign | -0.41 | Neutral | 0.979 | Probably Damaging | 0.821 | Possibly Damaging | 2.80 | Benign | 0.82 | Tolerated | 0.3462 | 0.4948 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2819G>C | G940A 2D AIThe SynGAP1 missense variant G940A 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 | 0.889439 | Disordered | 0.920635 | Binding | 0.383 | 0.902 | 0.625 | -5.356 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.163 | Likely Benign | 0.64 | Neutral | 0.004 | Benign | 0.012 | Benign | 2.85 | Benign | 0.89 | Tolerated | 0.3627 | 0.4831 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2828G>C | G943A 2D AIThe SynGAP1 missense variant G943A is reported in gnomAD (ID 6‑33443380‑G‑C) 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 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 unanimous benign predictions and lack of ClinVar pathogenicity, 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 | 0.973328 | Disordered | 0.860437 | Binding | 0.372 | 0.910 | 0.750 | 6-33443380-G-C | 3 | 1.86e-6 | -6.684 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.274 | Likely Benign | 0.10 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.87 | Benign | 0.89 | Tolerated | 4.32 | 4 | 0.3415 | 0.4957 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2831G>C | G944A 2D AIThe SynGAP1 missense variant G944A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.852408 | Binding | 0.360 | 0.923 | 0.750 | -6.397 | Likely Benign | 0.089 | Likely Benign | Likely Benign | 0.314 | Likely Benign | -0.61 | Neutral | 0.059 | Benign | 0.042 | Benign | 3.81 | Benign | 0.00 | Affected | 0.3352 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2837G>C | G946A 2D AIThe SynGAP1 missense variant G946A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while ESM1b is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for G946A, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985417 | Disordered | 0.845792 | Binding | 0.357 | 0.920 | 0.750 | -7.004 | In-Between | 0.079 | Likely Benign | Likely Benign | 0.191 | Likely Benign | 0.33 | Neutral | 0.649 | Possibly Damaging | 0.209 | Benign | 4.77 | Benign | 0.00 | Affected | 0.3378 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2840G>C | G947A 2D AIThe SynGAP1 missense variant G947A is listed in ClinVar (ID 1595137) with an “Uncertain” status and is present in gnomAD (variant ID 6‑33443392‑G‑C). 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 in the dataset predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign.” Foldetta results are not available. Overall, the computational evidence strongly favors a benign impact, which does not contradict the ClinVar “Uncertain” designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988695 | Disordered | 0.850554 | Binding | 0.358 | 0.919 | 0.750 | Conflicting | 3 | 6-33443392-G-C | 28 | 1.73e-5 | -6.511 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.156 | Likely Benign | -0.41 | Neutral | 0.224 | Benign | 0.131 | Benign | 4.97 | Benign | 0.10 | Tolerated | 4.32 | 4 | 0.3375 | 0.4957 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.2843G>C | G948A 2D AIThe SynGAP1 missense variant G948A 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 | 0.988505 | Disordered | 0.862121 | Binding | 0.365 | 0.919 | 0.750 | -5.627 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.189 | Likely Benign | 0.04 | Neutral | 0.288 | Benign | 0.103 | Benign | 4.64 | Benign | 0.39 | Tolerated | 0.3350 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2846G>C | G949A 2D AIThe SynGAP1 missense variant G949A 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Benign” (3 benign vs. 1 pathogenic votes). High‑accuracy methods confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also predicts benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, 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 | 0.988861 | Disordered | 0.874971 | Binding | 0.365 | 0.923 | 0.750 | -6.838 | Likely Benign | 0.072 | Likely Benign | Likely Benign | 0.274 | Likely Benign | -0.08 | Neutral | 0.779 | Possibly Damaging | 0.425 | Benign | 2.28 | Pathogenic | 0.08 | Tolerated | 0.3385 | 0.4414 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2849G>C | G950A 2D AIThe SynGAP1 missense variant G950A 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. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict, reflecting the majority of benign calls. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that 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 | 0.987317 | Disordered | 0.888649 | Binding | 0.368 | 0.923 | 0.750 | -6.557 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.339 | Likely Benign | -0.13 | Neutral | 0.059 | Benign | 0.061 | Benign | 2.28 | Pathogenic | 0.08 | Tolerated | 0.3343 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2855G>C | G952A 2D AIThe SynGAP1 missense variant G952A 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, so the pathogenic group is empty. 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, has no available result for this variant. ClinVar contains no entry for G952A, so there is no conflicting clinical annotation. Overall, the computational evidence indicates the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.985964 | Disordered | 0.910621 | Binding | 0.341 | 0.926 | 0.750 | -5.796 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.273 | Likely Benign | -0.20 | Neutral | 0.000 | Benign | 0.000 | Benign | 3.26 | Benign | 0.08 | Tolerated | 0.3309 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2863T>A | S955T 2D AIThe SynGAP1 missense variant S955T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S955T, 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 | 0.984871 | Disordered | 0.945325 | Binding | 0.350 | 0.924 | 0.750 | -4.717 | Likely Benign | 0.087 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -0.96 | Neutral | 0.451 | Benign | 0.265 | Benign | 2.38 | Pathogenic | 0.00 | Affected | 0.2184 | 0.5927 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2866T>A | S956T 2D AIThe SynGAP1 missense variant S956T 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, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote). Only FATHMM predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus also as likely benign; the Foldetta protein‑folding stability analysis is unavailable. Overall, the majority of evidence points to a benign impact for S956T, 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 | 0.984871 | Disordered | 0.957345 | Binding | 0.364 | 0.917 | 0.750 | -5.404 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.079 | Likely Benign | -0.45 | Neutral | 0.369 | Benign | 0.159 | Benign | 2.00 | Pathogenic | 0.08 | Tolerated | 0.2244 | 0.5727 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.287G>C | G96A 2D AIThe SynGAP1 missense variant G96A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.657645 | Disordered | 0.599491 | Binding | 0.335 | 0.871 | 0.625 | -3.669 | Likely Benign | 0.066 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -1.00 | Neutral | 0.092 | Benign | 0.007 | Benign | 4.23 | Benign | 0.00 | Affected | 0.4098 | 0.4212 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2903G>C | G968A 2D AIThe SynGAP1 missense variant G968A is predicted to be benign by all available in‑silico tools. Consensus predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all classify the change as benign. No tools predict pathogenicity, so the pathogenic group is empty. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized reports benign, and the SGM‑Consensus indicates “Likely 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 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 | 0.978316 | Disordered | 0.961360 | Binding | 0.327 | 0.896 | 0.750 | -4.721 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.33 | Neutral | 0.245 | Benign | 0.140 | Benign | 4.24 | Benign | 0.68 | Tolerated | 0.3401 | 0.5154 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2906G>C | G969A 2D AIThe SynGAP1 missense variant G969A 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 predicts benign, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “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 | 0.950334 | Disordered | 0.956572 | Binding | 0.405 | 0.898 | 0.750 | -4.693 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -0.36 | Neutral | 0.393 | Benign | 0.096 | Benign | 4.25 | Benign | 0.51 | Tolerated | 0.3414 | 0.5096 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2918G>C | G973A 2D AIThe SynGAP1 missense variant G973A is reported in gnomAD (ID 6‑33443470‑G‑C) 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 classify the substitution as benign. No tool predicts pathogenicity. The high‑accuracy consensus (SGM‑Consensus, derived from a 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, has no available result for this variant. Overall, the evidence strongly supports a benign classification, and this assessment 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 | 0.959498 | Binding | 0.390 | 0.897 | 0.625 | 6-33443470-G-C | 1 | 6.20e-7 | -3.847 | Likely Benign | 0.075 | Likely Benign | Likely Benign | 0.091 | Likely Benign | 0.14 | Neutral | 0.112 | Benign | 0.028 | Benign | 4.30 | Benign | 0.62 | Tolerated | 4.32 | 2 | 0.3405 | 0.5133 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2922C>A | D974E 2D AIThe SynGAP1 missense variant D974E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.617 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -0.63 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.26 | Benign | 0.05 | Affected | 0.2119 | 0.7516 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2922C>G | D974E 2D AIThe SynGAP1 missense variant D974E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.879233 | Disordered | 0.964377 | Binding | 0.389 | 0.897 | 0.625 | -3.617 | Likely Benign | 0.109 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -0.63 | Neutral | 0.036 | Benign | 0.026 | Benign | 4.26 | Benign | 0.05 | Affected | 0.2119 | 0.7516 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2942G>C | G981A 2D AIThe SynGAP1 missense variant G981A 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 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT, while AlphaMissense‑Default remains uncertain. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also predicts Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, 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 | 0.798249 | Disordered | 0.970320 | Binding | 0.275 | 0.897 | 0.625 | -3.374 | Likely Benign | 0.368 | Ambiguous | Likely Benign | 0.064 | Likely Benign | -0.95 | Neutral | 0.561 | Possibly Damaging | 0.376 | Benign | 3.95 | Benign | 0.00 | Affected | 0.3512 | 0.4925 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2948G>C | S983T 2D AIThe SynGAP1 missense variant S983T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign). High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus and Foldetta (which would combine FoldX‑MD and Rosetta outputs) are unavailable. Overall, the balance of evidence leans toward pathogenicity, with five tools supporting a deleterious effect versus four supporting benign. This prediction 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. | 0.707965 | Disordered | 0.960212 | Binding | 0.277 | 0.889 | 0.625 | -4.493 | Likely Benign | 0.588 | Likely Pathogenic | Likely Benign | 0.172 | Likely Benign | -1.65 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.08 | Pathogenic | 0.00 | Affected | 0.2042 | 0.5517 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.2954G>C | S985T 2D AIThe SynGAP1 missense variant S985T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. AlphaMissense‑Default is uncertain, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact for S985T, 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 | 0.720929 | Disordered | 0.941547 | Binding | 0.302 | 0.896 | 0.750 | -5.658 | Likely Benign | 0.475 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.54 | Benign | 0.00 | Affected | 0.1889 | 0.5844 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2961C>A | D987E 2D AIThe SynGAP1 missense variant D987E is reported in gnomAD (6‑33443513‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is 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 predictions points to a benign effect, 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 | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | 6-33443513-C-A | 1 | 6.20e-7 | -4.406 | Likely Benign | 0.425 | Ambiguous | Likely Benign | 0.124 | Likely Benign | -1.36 | Neutral | 0.049 | Benign | 0.044 | Benign | 2.64 | Benign | 0.04 | Affected | 4.32 | 2 | 0.1586 | 0.7239 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2961C>G | D987E 2D AIThe SynGAP1 missense variant D987E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized predicts Benign, SGM‑Consensus indicates Likely Benign, and Foldetta results are unavailable. Overall, the preponderance of evidence points to a benign effect for D987E, 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 | 0.823549 | Disordered | 0.919118 | Binding | 0.299 | 0.903 | 0.750 | -4.406 | Likely Benign | 0.425 | Ambiguous | Likely Benign | 0.124 | Likely Benign | -1.36 | Neutral | 0.049 | Benign | 0.044 | Benign | 2.64 | Benign | 0.04 | Affected | 4.32 | 2 | 0.1586 | 0.7239 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.2965T>A | S989T 2D AIThe SynGAP1 missense variant S989T is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict benign. Only two tools—polyPhen‑2 HumDiv and SIFT—suggest a pathogenic impact. The high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) classifies the variant as Likely Benign, and AlphaMissense‑Optimized also reports a benign outcome. No Foldetta stability data are available. 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 | 0.795062 | Disordered | 0.908835 | Binding | 0.296 | 0.911 | 0.750 | -3.995 | Likely Benign | 0.118 | Likely Benign | Likely Benign | 0.059 | Likely Benign | -1.48 | Neutral | 0.770 | Possibly Damaging | 0.396 | Benign | 2.66 | Benign | 0.00 | Affected | 0.1183 | 0.5377 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2968T>A | S990T 2D AIThe SynGAP1 missense variant S990T 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 | 0.816150 | Disordered | 0.902387 | Binding | 0.301 | 0.919 | 0.750 | -4.439 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.06 | Neutral | 0.001 | Benign | 0.007 | Benign | 2.89 | Benign | 1.00 | Tolerated | 0.1524 | 0.5598 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2972G>C | G991A 2D AIThe SynGAP1 missense variant G991A is catalogued in gnomAD (ID 6‑33443524‑G‑C) and has no ClinVar entry. All evaluated in silico predictors report a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized are unanimous in predicting benign. No tool indicates pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized is benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is “Likely Benign,” while Foldetta results are unavailable. Consequently, the variant is most likely benign based on current 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 | 0.745909 | Disordered | 0.911393 | Binding | 0.286 | 0.920 | 0.750 | 6-33443524-G-C | 1 | 6.20e-7 | -3.585 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.064 | Likely Benign | -0.83 | Neutral | 0.002 | Benign | 0.026 | Benign | 4.20 | Benign | 0.62 | Tolerated | 4.32 | 2 | 0.3522 | 0.4528 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2974G>A | V992I 2D AIThe SynGAP1 missense variant V992I is catalogued in gnomAD (ID 6‑33443526‑G‑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 indicates pathogenicity, 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) yields a Likely Benign verdict. Foldetta results are not available for this variant. Consequently, the variant is most likely benign, and this prediction 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 | 0.754692 | Disordered | 0.921728 | Binding | 0.331 | 0.917 | 0.750 | 6-33443526-G-A | 5 | 3.10e-6 | -3.851 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.052 | Likely Benign | -0.30 | Neutral | 0.302 | Benign | 0.089 | Benign | 4.20 | Benign | 0.29 | Tolerated | 4.32 | 2 | 0.0939 | 0.4541 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.2974G>C | V992L 2D AIThe SynGAP1 missense variant V992L 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 | 0.754692 | Disordered | 0.921728 | Binding | 0.331 | 0.917 | 0.750 | -2.333 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.060 | Likely Benign | -0.50 | Neutral | 0.086 | Benign | 0.038 | Benign | 4.24 | Benign | 0.16 | Tolerated | 0.1211 | 0.5202 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.2995T>A | S999T 2D AIThe SynGAP1 missense variant S999T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, 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 | 0.834292 | Disordered | 0.950682 | Binding | 0.262 | 0.897 | 0.625 | -3.961 | Likely Benign | 0.088 | Likely Benign | Likely Benign | 0.043 | Likely Benign | -0.94 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 2.69 | Benign | 0.04 | Affected | 0.1469 | 0.6651 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3008G>C | S1003T 2D AIThe SynGAP1 missense variant S1003T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in silico tools cluster around a benign effect: REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized all indicate benign, while the majority of pathogenic predictors—polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT—suggest a damaging impact. The AlphaMissense‑Default score is uncertain, and Foldetta stability analysis is unavailable. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments therefore lean toward a benign interpretation: AlphaMissense‑Optimized predicts benign, SGM‑Consensus is likely benign, and no Foldetta data is present. Overall, the computational evidence supports a benign classification, with no conflict with ClinVar status because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.947349 | Binding | 0.272 | 0.901 | 0.625 | -5.140 | Likely Benign | 0.493 | Ambiguous | Likely Benign | 0.115 | Likely Benign | -1.04 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.51 | Benign | 0.00 | Affected | 0.1864 | 0.6227 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3014G>C | S1005T 2D AIThe SynGAP1 missense variant S1005T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and AlphaMissense‑Optimized, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 majority of computational evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.812494 | Disordered | 0.936602 | Binding | 0.261 | 0.897 | 0.750 | -6.015 | Likely Benign | 0.454 | Ambiguous | Likely Benign | 0.120 | Likely Benign | -1.30 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.66 | Benign | 0.00 | Affected | 0.1600 | 0.4937 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3020G>C | S1007T 2D AIThe SynGAP1 missense variant S1007T is reported in ClinVar as “Not submitted” (no ClinVar entry) and is present in gnomAD (allele ID 6‑33443572‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and SIFT. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM Consensus as likely benign; Foldetta results are not available. Based on the overall consensus of the available predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.925648 | Binding | 0.295 | 0.899 | 0.750 | 6-33443572-G-C | -4.719 | Likely Benign | 0.303 | Likely Benign | Likely Benign | 0.071 | Likely Benign | -1.24 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.68 | Benign | 0.03 | Affected | 3.77 | 5 | 0.1796 | 0.5550 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3024T>A | D1008E 2D AIThe SynGAP1 D1008E missense variant is catalogued in gnomAD (6‑33443576‑T‑A) 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 both predict a pathogenic outcome. AlphaMissense‑Default remains uncertain, providing no definitive signal. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, and the SGM‑Consensus also reports it as likely benign. No Foldetta stability analysis is available, so it does not influence the overall assessment. Based on the preponderance of evidence from both general and high‑accuracy predictors, 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 | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | 6-33443576-T-A | 1 | 6.20e-7 | -2.809 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -0.53 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.93 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2315 | 0.6303 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.3024T>G | D1008E 2D AIThe SynGAP1 missense variant D1008E is listed in gnomAD (ID 6‑33443576‑T‑G) 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). Tools that predict a pathogenic effect are PolyPhen‑2 HumDiv and PolyPhen‑2 HumVar. AlphaMissense‑Default is uncertain, and Foldetta results are unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta provides no data. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the absence of a ClinVar pathogenic classification, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.694846 | Disordered | 0.919416 | Binding | 0.280 | 0.899 | 0.625 | 6-33443576-T-G | -2.809 | Likely Benign | 0.428 | Ambiguous | Likely Benign | 0.151 | Likely Benign | -0.53 | Neutral | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 2.93 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.2315 | 0.6303 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3032G>C | G1011A 2D AIThe SynGAP1 missense variant G1011A is catalogued in gnomAD (ID 6‑33443584‑G‑C) 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 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 results are unavailable. Based on the collective predictions, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.834292 | Disordered | 0.898380 | Binding | 0.332 | 0.869 | 0.625 | 6-33443584-G-C | -4.349 | Likely Benign | 0.097 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.04 | Neutral | 0.139 | Benign | 0.089 | Benign | 2.89 | Benign | 0.64 | Tolerated | 3.77 | 5 | 0.3641 | 0.4571 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3037T>A | S1013T 2D AIThe SynGAP1 missense variant S1013T is not reported in ClinVar and is absent from gnomAD, indicating no documented population frequency. 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 (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.823549 | Disordered | 0.899570 | Binding | 0.308 | 0.846 | 0.625 | -4.245 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.96 | Neutral | 0.069 | Benign | 0.072 | Benign | 2.70 | Benign | 0.26 | Tolerated | 0.1812 | 0.6039 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3041G>C | G1014A 2D AIThe SynGAP1 missense variant G1014A is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess sequence conservation and functional impact (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) all classify the variant as benign. No tool predicts pathogenicity. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports “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. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.771762 | Disordered | 0.914808 | Binding | 0.293 | 0.835 | 0.625 | -3.520 | Likely Benign | 0.114 | Likely Benign | Likely Benign | 0.039 | Likely Benign | -1.06 | Neutral | 0.025 | Benign | 0.022 | Benign | 2.78 | Benign | 0.36 | Tolerated | 0.3677 | 0.4682 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3048C>A | D1016E 2D AIThe SynGAP1 missense variant D1016E is reported in ClinVar (ID 3803472.0) as benign and is present in gnomAD (variant ID 6‑33443600‑C‑A). 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 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 “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 overwhelmingly supports a benign effect, aligning with the ClinVar benign classification and showing no contradiction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | Likely Benign | 1 | 6-33443600-C-A | 2 | 1.24e-6 | -3.422 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 0.2237 | 0.6898 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3048C>G | D1016E 2D AIThe SynGAP1 missense variant D1016E 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, so they do not influence the overall assessment. **Thus, the variant is most likely benign, 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 | 0.801317 | Disordered | 0.944705 | Binding | 0.323 | 0.811 | 0.625 | -3.422 | Likely Benign | 0.216 | Likely Benign | Likely Benign | 0.017 | Likely Benign | -0.37 | Neutral | 0.008 | Benign | 0.028 | Benign | 2.64 | Benign | 0.65 | Tolerated | 3.77 | 5 | 0.2237 | 0.6898 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.3067T>A | S1023T 2D AIThe SynGAP1 missense variant S1023T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, 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) also yields a benign prediction, and Foldetta results are unavailable. Overall, the majority of high‑confidence tools predict a benign impact, and there is no conflict with ClinVar status. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.831250 | Disordered | 0.990262 | Binding | 0.322 | 0.750 | 0.500 | -5.573 | Likely Benign | 0.360 | Ambiguous | Likely Benign | 0.092 | Likely Benign | -1.62 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.49 | Pathogenic | 0.04 | Affected | 0.1299 | 0.5370 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3078C>A | D1026E 2D AIThe SynGAP1 missense variant D1026E is listed in ClinVar (ID 4746138) as benign and is not reported in gnomAD. 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 tool predicts pathogenicity. Grouping by agreement, all predictors fall into the benign category, with no pathogenic calls. 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) also 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 computational evidence strongly supports a benign classification, fully consistent with the ClinVar designation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | Benign | 1 | -3.431 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.73 | Benign | 0.56 | Tolerated | 0.1449 | 0.4783 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.3078C>G | D1026E 2D AIThe SynGAP1 missense variant D1026E is not reported in ClinVar and is absent from gnomAD. All available 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 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) indicates a likely benign effect. 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 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 | 0.894241 | Disordered | 0.993931 | Binding | 0.324 | 0.739 | 0.500 | -3.431 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.37 | Neutral | 0.001 | Benign | 0.005 | Benign | 2.73 | Benign | 0.56 | Tolerated | 0.1449 | 0.4783 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.308G>C | G103A 2D AIThe SynGAP1 missense variant G103A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the single pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the majority of evidence 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 | 0.795062 | Disordered | 0.687376 | Binding | 0.381 | 0.877 | 0.625 | -3.549 | Likely Benign | 0.092 | Likely Benign | Likely Benign | 0.118 | Likely Benign | -0.08 | Neutral | 0.008 | Benign | 0.008 | Benign | 4.31 | Benign | 0.00 | Affected | 0.3941 | 0.3784 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3097T>A | S1033T 2D AIThe SynGAP1 missense variant S1033T 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, 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 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 majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.993473 | Binding | 0.294 | 0.737 | 0.625 | -3.702 | Likely Benign | 0.140 | Likely Benign | Likely Benign | 0.029 | Likely Benign | -0.05 | Neutral | 0.568 | Possibly Damaging | 0.171 | Benign | 2.73 | Benign | 0.58 | Tolerated | 0.1379 | 0.6089 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3119G>C | G1040A 2D AIThe SynGAP1 missense variant G1040A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are REVEL and FATHMM, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign prediction (2 benign vs. 1 pathogenic). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation, as the variant is not yet classified in that database. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.964893 | Disordered | 0.973805 | Binding | 0.332 | 0.816 | 0.625 | -2.625 | Likely Benign | 0.409 | Ambiguous | Likely Benign | 0.606 | Likely Pathogenic | -1.65 | Neutral | 0.114 | Benign | 0.030 | Benign | -0.74 | Pathogenic | 0.30 | Tolerated | 0.3246 | 0.5331 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3139T>A | S1047T 2D AIThe SynGAP1 missense variant S1047T 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 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 is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.963420 | Disordered | 0.933764 | Binding | 0.409 | 0.909 | 0.750 | -4.222 | Likely Benign | 0.070 | Likely Benign | Likely Benign | 0.029 | Likely Benign | 0.23 | Neutral | 0.069 | Benign | 0.049 | Benign | 2.63 | Benign | 0.63 | Tolerated | 0.1796 | 0.6265 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.313T>A | S105T 2D AIThe SynGAP1 missense variant S105T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign effect. AlphaMissense‑Optimized independently scores the variant as 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 assessment does not contradict any ClinVar annotation (none exists). Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.788093 | Disordered | 0.669201 | Binding | 0.364 | 0.870 | 0.625 | -4.166 | Likely Benign | 0.132 | Likely Benign | Likely Benign | 0.055 | Likely Benign | -0.54 | Neutral | 0.012 | Benign | 0.007 | Benign | 4.06 | Benign | 0.00 | Affected | 0.1583 | 0.5212 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3143G>C | G1048A 2D AISynGAP1 missense variant G1048A is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only polyPhen‑2 HumDiv predicts it as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” status. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the consensus of available predictions indicates that G1048A is most likely benign, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.977651 | Disordered | 0.923876 | Binding | 0.346 | 0.916 | 0.750 | -4.821 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.456 | Likely Benign | -0.14 | Neutral | 0.573 | Possibly Damaging | 0.358 | Benign | 2.57 | Benign | 0.64 | Tolerated | 0.3301 | 0.5138 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3149G>C | G1050A 2D AIThe SynGAP1 missense variant G1050A 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 ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.906802 | Binding | 0.370 | 0.928 | 0.875 | -5.514 | Likely Benign | 0.074 | Likely Benign | Likely Benign | 0.047 | Likely Benign | 0.18 | Neutral | 0.000 | Benign | 0.004 | Benign | 2.68 | Benign | 1.00 | Tolerated | 0.3349 | 0.5133 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3152G>C | G1051A 2D AIThe SynGAP1 missense variant G1051A is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote) is benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of computational evidence indicates a benign effect, and this conclusion does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.987317 | Disordered | 0.900141 | Binding | 0.358 | 0.936 | 0.875 | -6.406 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.406 | Likely Benign | -0.14 | Neutral | 0.009 | Benign | 0.004 | Benign | -0.74 | Pathogenic | 1.00 | Tolerated | 0.3353 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3155G>C | G1052A 2D AIThe SynGAP1 missense variant G1052A 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, creating a single discordant signal. 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 reports 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 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 | 0.984420 | Disordered | 0.892068 | Binding | 0.367 | 0.938 | 0.875 | -6.945 | Likely Benign | 0.086 | Likely Benign | Likely Benign | 0.382 | Likely Benign | -0.14 | Neutral | 0.649 | Possibly Damaging | 0.287 | Benign | 3.93 | Benign | 1.00 | Tolerated | 0.3259 | 0.4949 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3158G>C | S1053T 2D AIThe SynGAP1 missense variant S1053T 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 reinforce this view: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is also likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the preponderance of evidence points to a benign impact for S1053T, 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 | 0.981594 | Disordered | 0.885608 | Binding | 0.399 | 0.944 | 0.875 | -6.209 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.223 | Likely Benign | -0.25 | Neutral | 0.625 | Possibly Damaging | 0.249 | Benign | 5.32 | Benign | 0.70 | Tolerated | 0.2055 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3161G>C | G1054A 2D AIThe SynGAP1 missense variant G1054A is catalogued in gnomAD (ID 6‑33443713‑G‑C) 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 change as benign. No tool predicts pathogenicity, so the pathogenic‑prediction group is empty. 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, has no reported result for this variant, so its status is unavailable. Based on the unanimous benign predictions and the lack of any ClinVar pathogenic classification, 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 | 0.983019 | Disordered | 0.878015 | Binding | 0.389 | 0.936 | 0.875 | 6-33443713-G-C | -6.786 | Likely Benign | 0.078 | Likely Benign | Likely Benign | 0.243 | Likely Benign | -0.05 | Neutral | 0.288 | Benign | 0.071 | Benign | 4.03 | Benign | 1.00 | Tolerated | 3.77 | 5 | 0.3305 | 0.5144 | 0 | 1 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3164G>C | G1055A 2D AIThe SynGAP1 missense variant G1055A 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 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 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 | 0.982235 | Disordered | 0.872113 | Binding | 0.379 | 0.935 | 0.875 | -6.835 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.244 | Likely Benign | 0.15 | Neutral | 0.649 | Possibly Damaging | 0.148 | Benign | 3.30 | Benign | 1.00 | Tolerated | 0.3350 | 0.5144 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3167G>C | G1056A 2D AIThe SynGAP1 missense variant G1056A is not 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, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only FATHMM predicts a pathogenic outcome, while ESM1b remains uncertain. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a benign consensus (2 benign vs. 1 pathogenic, with one uncertain). Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence indicates that the variant is most likely benign, and this conclusion does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.988291 | Disordered | 0.868632 | Binding | 0.402 | 0.935 | 0.875 | -7.458 | In-Between | 0.086 | Likely Benign | Likely Benign | 0.325 | Likely Benign | -0.25 | Neutral | 0.264 | Benign | 0.097 | Benign | 1.85 | Pathogenic | 0.49 | Tolerated | 0.3325 | 0.4957 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3170G>C | S1057T 2D AIThe SynGAP1 missense variant S1057T 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 (majority vote) 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 is consistent with the lack of ClinVar evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.988291 | Disordered | 0.869507 | Binding | 0.413 | 0.927 | 0.875 | -6.375 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.241 | Likely Benign | -0.18 | Neutral | 0.625 | Possibly Damaging | 0.170 | Benign | 5.26 | Benign | 0.60 | Tolerated | 0.2289 | 0.5976 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3173G>C | G1058A 2D AIThe SynGAP1 missense variant G1058A 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 | 0.980739 | Disordered | 0.885724 | Binding | 0.407 | 0.929 | 0.875 | -6.823 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.159 | Likely Benign | 0.21 | Neutral | 0.000 | Benign | 0.002 | Benign | 5.29 | Benign | 0.55 | Tolerated | 0.3288 | 0.5144 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3176G>C | G1059A 2D AIThe SynGAP1 missense variant G1059A is listed in ClinVar (ID 1420036.0) with an “Uncertain” clinical significance and is present in gnomAD (variant ID 6‑33443728‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Overall, the majority of computational evidence supports a benign impact for G1059A, which does not contradict the ClinVar “Uncertain” status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.983019 | Disordered | 0.898939 | Binding | 0.399 | 0.926 | 0.875 | Uncertain | 1 | 6-33443728-G-C | 4 | 2.49e-6 | -6.754 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.329 | Likely Benign | -0.17 | Neutral | 0.001 | Benign | 0.002 | Benign | 2.56 | Benign | 0.00 | Affected | 4.32 | 2 | 0.3295 | 0.4944 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3179G>C | G1060A 2D AIThe SynGAP1 missense variant G1060A 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, creating a single discordant signal. 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 reports 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 is consistent with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.979242 | Disordered | 0.913048 | Binding | 0.407 | 0.928 | 0.875 | -6.539 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.341 | Likely Benign | 0.30 | Neutral | 0.664 | Possibly Damaging | 0.283 | Benign | 2.69 | Benign | 0.98 | Tolerated | 0.3335 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3182G>C | G1061A 2D AIThe SynGAP1 missense variant G1061A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are unavailable. Based on the preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.978672 | Disordered | 0.926729 | Binding | 0.394 | 0.923 | 0.875 | -6.328 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.244 | Likely Benign | -0.34 | Neutral | 0.004 | Benign | 0.002 | Benign | 4.01 | Benign | 0.00 | Affected | 0.3289 | 0.5133 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3185G>C | G1062A 2D AIThe SynGAP1 missense variant G1062A 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 | 0.976962 | Disordered | 0.936972 | Binding | 0.368 | 0.917 | 0.875 | -6.124 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.350 | Likely Benign | 0.20 | Neutral | 0.059 | Benign | 0.028 | Benign | 4.20 | Benign | 0.51 | Tolerated | 0.3305 | 0.5144 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3188G>C | G1063A 2D AIThe SynGAP1 missense variant G1063A 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 | 0.975134 | Disordered | 0.945784 | Binding | 0.394 | 0.913 | 0.875 | -5.373 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.045 | Likely Benign | 0.33 | Neutral | 0.000 | Benign | 0.002 | Benign | 4.30 | Benign | 0.12 | Tolerated | 0.3348 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3212G>C | G1071A 2D AIThe SynGAP1 missense variant G1071A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also indicates likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to 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 | 0.919029 | Disordered | 0.983740 | Binding | 0.313 | 0.905 | 0.875 | -1.825 | Likely Benign | 0.229 | Likely Benign | Likely Benign | 0.070 | Likely Benign | -1.34 | Neutral | 0.025 | Benign | 0.022 | Benign | 4.12 | Benign | 0.05 | Affected | 0.3376 | 0.5084 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3217T>A | S1073T 2D AIThe SynGAP1 missense variant S1073T 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. 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 | 0.916840 | Disordered | 0.985818 | Binding | 0.313 | 0.905 | 0.750 | -5.203 | Likely Benign | 0.169 | Likely Benign | Likely Benign | 0.161 | Likely Benign | -0.26 | Neutral | 0.025 | Benign | 0.026 | Benign | 4.06 | Benign | 0.55 | Tolerated | 0.1696 | 0.6509 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3232G>A | V1078I 2D AIThe SynGAP1 missense variant V1078I 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 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 consensus methods suggests that V1078I 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 | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -3.652 | Likely Benign | 0.200 | Likely Benign | Likely Benign | 0.120 | Likely Benign | -0.16 | Neutral | 0.625 | Possibly Damaging | 0.266 | Benign | 3.98 | Benign | 0.07 | Tolerated | 0.0771 | 0.4693 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3232G>C | V1078L 2D AIThe SynGAP1 missense variant V1078L 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 results are unavailable, so they do not influence the assessment. Overall, the collective evidence strongly suggests that V1078L 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 | 0.882776 | Disordered | 0.986989 | Binding | 0.294 | 0.898 | 0.750 | -2.547 | Likely Benign | 0.523 | Ambiguous | Likely Benign | 0.091 | Likely Benign | -0.16 | Neutral | 0.451 | Benign | 0.209 | Benign | 4.13 | Benign | 0.56 | Tolerated | 0.0889 | 0.5349 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3236G>C | S1079T 2D AIThe SynGAP1 missense variant S1079T is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. 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, and PROVEAN) reports it as Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the computational evidence strongly suggests the variant is most likely benign, and this conclusion does not contradict the ClinVar status, which currently has no entry for S1079T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.919029 | Disordered | 0.983887 | Binding | 0.307 | 0.900 | 0.750 | -3.225 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.023 | Likely Benign | -1.28 | Neutral | 0.001 | Benign | 0.003 | Benign | 3.91 | Benign | 0.00 | Affected | 0.1283 | 0.5920 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3259T>A | S1087T 2D AIThe SynGAP1 missense variant S1087T 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, 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 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 is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.974805 | Binding | 0.357 | 0.891 | 1.000 | -4.455 | Likely Benign | 0.128 | Likely Benign | Likely Benign | 0.044 | Likely Benign | -1.01 | Neutral | 0.790 | Possibly Damaging | 0.266 | Benign | 2.66 | Benign | 0.25 | Tolerated | 0.1333 | 0.6503 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3263G>C | S1088T 2D AIThe SynGAP1 missense variant S1088T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability result is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.910643 | Disordered | 0.975261 | Binding | 0.336 | 0.889 | 1.000 | -4.569 | Likely Benign | 0.295 | Likely Benign | Likely Benign | 0.175 | Likely Benign | -1.32 | Neutral | 0.979 | Probably Damaging | 0.973 | Probably Damaging | 2.71 | Benign | 0.04 | Affected | 0.2048 | 0.6514 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3266G>C | G1089A 2D AIThe SynGAP1 missense variant G1089A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this is consistent with the lack of ClinVar annotation—there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.976771 | Binding | 0.366 | 0.890 | 1.000 | -2.864 | Likely Benign | 0.224 | Likely Benign | Likely Benign | 0.142 | Likely Benign | -1.73 | Neutral | 0.186 | Benign | 0.055 | Benign | 2.45 | Pathogenic | 0.02 | Affected | 0.3475 | 0.5331 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.326G>C | S109T 2D AIThe SynGAP1 missense variant S109T is catalogued in gnomAD (6‑33432191‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all report benign or likely benign. Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments confirm the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus, derived from the majority of the high‑accuracy predictors, is benign. Foldetta, a protein‑folding stability method that integrates FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence indicates that S109T 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 | 0.622677 | Disordered | 0.669335 | Binding | 0.328 | 0.864 | 0.750 | 6-33432191-G-C | 2 | 1.24e-6 | -4.065 | Likely Benign | 0.449 | Ambiguous | Likely Benign | 0.090 | Likely Benign | -1.19 | Neutral | 0.231 | Benign | 0.050 | Benign | 3.59 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1519 | 0.5212 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.3280T>A | S1094T 2D AIThe SynGAP1 missense variant S1094T 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 | 0.938133 | Disordered | 0.981352 | Binding | 0.358 | 0.877 | 1.000 | -4.009 | Likely Benign | 0.194 | Likely Benign | Likely Benign | 0.077 | Likely Benign | -0.57 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 2.59 | Benign | 0.16 | Tolerated | 0.1874 | 0.6902 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.328G>A | V110I 2D AIThe SynGAP1 missense variant V110I 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 | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -4.409 | Likely Benign | 0.103 | Likely Benign | Likely Benign | 0.058 | Likely Benign | -0.10 | Neutral | 0.012 | Benign | 0.006 | Benign | 4.26 | Benign | 0.52 | Tolerated | 0.0875 | 0.4485 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.328G>C | V110L 2D AIThe SynGAP1 missense variant V110L 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. 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 evidence overwhelmingly supports a benign impact for V110L, 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 | 0.622677 | Disordered | 0.665934 | Binding | 0.347 | 0.860 | 0.750 | -3.024 | Likely Benign | 0.357 | Ambiguous | Likely Benign | 0.058 | Likely Benign | -0.71 | Neutral | 0.158 | Benign | 0.025 | Benign | 4.20 | Benign | 0.50 | Tolerated | 0.1165 | 0.5145 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3293G>C | S1098T 2D AIThe SynGAP1 missense variant S1098T 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. 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 | 0.919029 | Disordered | 0.973030 | Binding | 0.337 | 0.855 | 1.000 | -4.144 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.18 | Neutral | 0.224 | Benign | 0.120 | Benign | 2.76 | Benign | 0.88 | Tolerated | 0.1706 | 0.6653 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3299G>C | G1100A 2D AIThe SynGAP1 missense variant G1100A 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, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. 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 not available. Overall, the majority of predictions (six benign vs. four pathogenic) lean toward a benign interpretation. Thus, the variant is most likely benign based on current computational evidence, 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 | 0.882776 | Disordered | 0.972009 | Binding | 0.360 | 0.865 | 0.875 | -2.862 | Likely Benign | 0.107 | Likely Benign | Likely Benign | 0.146 | Likely Benign | -0.95 | Neutral | 0.943 | Possibly Damaging | 0.667 | Possibly Damaging | 2.01 | Pathogenic | 0.05 | Affected | 0.3442 | 0.5154 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.32G>C | G11A 2D AIThe SynGAP1 missense variant G11A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.444081 | Structured | 0.501027 | Binding | 0.348 | 0.915 | 0.375 | -3.611 | Likely Benign | 0.106 | Likely Benign | Likely Benign | 0.072 | Likely Benign | -0.28 | Neutral | 0.105 | Benign | 0.007 | Benign | 4.00 | Benign | 0.00 | Affected | 0.4045 | 0.5440 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3323G>C | S1108T 2D AIThe SynGAP1 missense variant S1108T 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.852992 | Disordered | 0.949221 | Binding | 0.324 | 0.886 | 0.875 | -5.710 | Likely Benign | 0.105 | Likely Benign | Likely Benign | 0.078 | Likely Benign | -1.49 | Neutral | 0.393 | Benign | 0.239 | Benign | 2.56 | Benign | 0.25 | Tolerated | 0.1304 | 0.5365 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3329G>C | S1110T 2D AIThe SynGAP1 missense variant S1110T 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 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Based on the preponderance of benign predictions and the consensus from high‑accuracy tools, the variant is most likely benign, and this assessment does not contradict any ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.912647 | Disordered | 0.934156 | Binding | 0.346 | 0.892 | 0.875 | -3.989 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.032 | Likely Benign | -1.76 | Neutral | 0.001 | Benign | 0.003 | Benign | 2.21 | Pathogenic | 0.04 | Affected | 0.1581 | 0.6224 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3338G>C | G1113A 2D AIThe SynGAP1 missense variant G1113A 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 | 0.905695 | Disordered | 0.900456 | Binding | 0.327 | 0.910 | 0.875 | -4.714 | Likely Benign | 0.077 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -1.15 | Neutral | 0.798 | Possibly Damaging | 0.433 | Benign | 2.58 | Benign | 0.50 | Tolerated | 0.3444 | 0.5342 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3341G>C | S1114T 2D AIThe SynGAP1 missense variant S1114T 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 because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.895196 | Binding | 0.295 | 0.908 | 0.875 | -5.919 | Likely Benign | 0.071 | Likely Benign | Likely Benign | 0.038 | Likely Benign | -0.87 | Neutral | 0.071 | Benign | 0.078 | Benign | 2.69 | Benign | 0.10 | Tolerated | 0.1424 | 0.6095 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3347G>C | G1116A 2D AIThe SynGAP1 missense variant G1116A 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 | 0.889439 | Disordered | 0.873279 | Binding | 0.320 | 0.909 | 0.750 | -5.753 | Likely Benign | 0.079 | Likely Benign | Likely Benign | 0.288 | Likely Benign | -0.24 | Neutral | 0.010 | Benign | 0.022 | Benign | 4.08 | Benign | 0.24 | Tolerated | 0.3417 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3350G>C | G1117A 2D AIThe SynGAP1 missense variant G1117A 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 | 0.882776 | Disordered | 0.853192 | Binding | 0.323 | 0.914 | 0.750 | -6.514 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.183 | Likely Benign | -0.41 | Neutral | 0.152 | Benign | 0.071 | Benign | 4.61 | Benign | 0.23 | Tolerated | 0.3545 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3353G>C | S1118T 2D AIThe SynGAP1 missense variant S1118T 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, 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; Foldetta results are unavailable. Overall, the preponderance of evidence indicates 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 | 0.876521 | Disordered | 0.828802 | Binding | 0.310 | 0.919 | 0.750 | -6.063 | Likely Benign | 0.067 | Likely Benign | Likely Benign | 0.196 | Likely Benign | -0.67 | Neutral | 0.790 | Possibly Damaging | 0.433 | Benign | 5.18 | Benign | 0.10 | Tolerated | 0.2066 | 0.5587 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3356G>C | G1119A 2D AIThe SynGAP1 missense variant G1119A 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 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 | 0.818538 | Binding | 0.339 | 0.928 | 0.875 | -6.703 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.201 | Likely Benign | -0.33 | Neutral | 0.393 | Benign | 0.187 | Benign | 3.93 | Benign | 1.00 | Tolerated | 0.3591 | 0.4957 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3359G>C | G1120A 2D AIThe SynGAP1 missense variant G1120A 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, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a pathogenic outcome; ESM1b is uncertain, and the SGM‑Consensus (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 a benign likelihood. Foldetta results are unavailable. Overall, the consensus of available predictions indicates that G1120A is most likely benign, and this conclusion does not contradict any ClinVar status because none is assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.871313 | Disordered | 0.804931 | Binding | 0.335 | 0.925 | 0.875 | -7.192 | In-Between | 0.082 | Likely Benign | Likely Benign | 0.243 | Likely Benign | -0.39 | Neutral | 0.264 | Benign | 0.139 | Benign | 3.64 | Benign | 0.28 | Tolerated | 0.3435 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.335G>C | G112A 2D AIThe SynGAP1 missense variant G112A is listed in ClinVar with an uncertain significance (ClinVar ID 1425533.0) and is present in gnomAD (6‑33432200‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized is benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also benign. Foldetta results are unavailable. Overall, the majority of computational evidence indicates that the variant is most likely benign, which is consistent with its ClinVar status of uncertain significance. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.728858 | Disordered | 0.640153 | Binding | 0.332 | 0.867 | 0.750 | Uncertain | 1 | 6-33432200-G-C | 15 | 9.30e-6 | -2.456 | Likely Benign | 0.119 | Likely Benign | Likely Benign | 0.114 | Likely Benign | -2.34 | Neutral | 0.231 | Benign | 0.054 | Benign | 4.07 | Benign | 0.00 | Affected | 3.61 | 5 | 0.3817 | 0.4429 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3362G>C | S1121T 2D AIThe SynGAP1 missense variant S1121T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Based on the collective evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none is provided). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.894241 | Disordered | 0.810024 | Binding | 0.365 | 0.935 | 0.875 | -6.442 | Likely Benign | 0.069 | Likely Benign | Likely Benign | 0.105 | Likely Benign | -0.23 | Neutral | 0.011 | Benign | 0.026 | Benign | 5.45 | Benign | 0.00 | Affected | 0.2108 | 0.5582 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3365G>C | G1122A 2D AIThe SynGAP1 missense variant G1122A 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 evidence strongly supports a benign classification, and there is no conflict with ClinVar status, which simply lacks an entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.814918 | Binding | 0.357 | 0.932 | 0.875 | -6.692 | Likely Benign | 0.076 | Likely Benign | Likely Benign | 0.168 | Likely Benign | -0.52 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.52 | Benign | 0.62 | Tolerated | 0.3487 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3368G>C | G1123A 2D AIThe SynGAP1 missense variant G1123A 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 methods. High‑accuracy tools 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 | 0.837511 | Disordered | 0.827246 | Binding | 0.346 | 0.934 | 0.875 | -6.720 | Likely Benign | 0.082 | Likely Benign | Likely Benign | 0.240 | Likely Benign | -0.55 | Neutral | 0.264 | Benign | 0.103 | Benign | 4.38 | Benign | 1.00 | Tolerated | 0.3544 | 0.4944 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3371G>C | G1124A 2D AIThe SynGAP1 missense variant G1124A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized scores the variant as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates “Likely Benign,” and the Foldetta stability analysis is unavailable. Taken together, the overwhelming majority of computational evidence classifies G1124A as 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 | 0.837511 | Disordered | 0.833401 | Binding | 0.341 | 0.931 | 0.875 | -6.608 | Likely Benign | 0.084 | Likely Benign | Likely Benign | 0.199 | Likely Benign | -0.39 | Neutral | 0.059 | Benign | 0.041 | Benign | 4.81 | Benign | 0.02 | Affected | 0.3494 | 0.5138 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3374G>C | G1125A 2D AIThe SynGAP1 missense variant G1125A is listed in ClinVar with an “Uncertain” status and is present in gnomAD (6‑33443926‑G‑C). Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized; the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports a likely benign outcome. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from the four high‑accuracy tools) is 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 | 0.834292 | Disordered | 0.835839 | Binding | 0.339 | 0.923 | 0.875 | Uncertain | 1 | 6-33443926-G-C | 1 | 6.68e-7 | -6.569 | Likely Benign | 0.083 | Likely Benign | Likely Benign | 0.232 | Likely Benign | -0.60 | Neutral | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 4.60 | Benign | 0.11 | Tolerated | 3.77 | 5 | 0.3395 | 0.5138 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3377G>C | G1126A 2D AIThe SynGAP1 missense variant G1126A 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 | 0.894241 | Disordered | 0.837209 | Binding | 0.345 | 0.918 | 0.875 | -6.402 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.228 | Likely Benign | -0.63 | Neutral | 0.124 | Benign | 0.061 | Benign | 4.83 | Benign | 0.56 | Tolerated | 0.3505 | 0.5333 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3380G>C | G1127A 2D AIThe SynGAP1 missense variant G1127A is listed in ClinVar (ID 426748.0) with an uncertain significance status and is present in gnomAD (variant ID 6‑33443932‑G‑C). 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. 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 combining FoldX‑MD and Rosetta outputs, did not provide a result for this variant, so its status is unavailable. Overall, the evidence strongly supports a benign classification, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.899122 | Disordered | 0.852422 | Binding | 0.344 | 0.915 | 0.875 | Conflicting | 4 | 6-33443932-G-C | 4 | 2.68e-6 | -5.949 | Likely Benign | 0.080 | Likely Benign | Likely Benign | 0.164 | Likely Benign | -0.43 | Neutral | 0.001 | Benign | 0.002 | Benign | 4.83 | Benign | 1.00 | Tolerated | 4.32 | 4 | 0.3420 | 0.4933 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||
| c.3383G>C | G1128A 2D AIThe SynGAP1 missense variant G1128A 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 results are unavailable. Based on the collective predictions, the variant is most likely benign, and this conclusion is consistent with the absence of a ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.865136 | Binding | 0.309 | 0.911 | 0.875 | -5.015 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.209 | Likely Benign | -0.26 | Neutral | 0.009 | Benign | 0.008 | Benign | 4.47 | Benign | 0.46 | Tolerated | 0.3588 | 0.5252 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.338G>C | G113A 2D AIThe SynGAP1 missense variant G113A 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. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely benign outcome. No tool predicts pathogenicity. High‑accuracy assessments corroborate this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates likely benign. Foldetta results are not available for this variant. Based on the collective evidence, 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 | 0.784345 | Disordered | 0.639486 | Binding | 0.350 | 0.870 | 0.750 | -3.552 | Likely Benign | 0.162 | Likely Benign | Likely Benign | 0.045 | Likely Benign | -0.61 | Neutral | 0.131 | Benign | 0.039 | Benign | 4.20 | Benign | 0.22 | Tolerated | 0.4059 | 0.4684 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3394T>A | S1132T 2D AIThe SynGAP1 missense variant S1132T 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 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 | 0.919029 | Disordered | 0.845506 | Binding | 0.289 | 0.894 | 0.750 | -3.700 | Likely Benign | 0.073 | Likely Benign | Likely Benign | 0.190 | Likely Benign | -0.71 | Neutral | 0.011 | Benign | 0.017 | Benign | 5.45 | Benign | 0.50 | Tolerated | 0.1552 | 0.6309 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3412T>A | S1138T 2D AIThe SynGAP1 missense variant S1138T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. In contrast, polyPhen‑2 (both HumDiv and HumVar models) predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, 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 for S1138T, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.891961 | Disordered | 0.738250 | Binding | 0.346 | 0.869 | 1.000 | -5.243 | Likely Benign | 0.081 | Likely Benign | Likely Benign | 0.370 | Likely Benign | -1.21 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 5.45 | Benign | 0.23 | Tolerated | 0.1844 | 0.6653 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3424T>A | S1142T 2D AIThe SynGAP1 missense variant S1142T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact, 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 | 0.919029 | Disordered | 0.719935 | Binding | 0.276 | 0.844 | 1.000 | -3.712 | Likely Benign | 0.100 | Likely Benign | Likely Benign | 0.106 | Likely Benign | -1.63 | Neutral | 0.611 | Possibly Damaging | 0.324 | Benign | 2.69 | Benign | 0.00 | Affected | 0.1548 | 0.6427 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3451T>A | S1151T 2D AIThe SynGAP1 missense variant S1151T 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. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic effect. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none is present). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.741537 | Disordered | 0.805072 | Binding | 0.394 | 0.839 | 0.625 | -3.874 | Likely Benign | 0.124 | Likely Benign | Likely Benign | 0.080 | Likely Benign | -0.06 | Neutral | 0.798 | Possibly Damaging | 0.535 | Possibly Damaging | 2.72 | Benign | 0.30 | Tolerated | 0.1450 | 0.5903 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3463G>C | V1155L 2D AIThe SynGAP1 missense variant V1155L is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and both AlphaMissense models. When predictions are grouped by agreement, the benign set includes five tools and the pathogenic set includes four. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence, especially from the high‑accuracy AlphaMissense‑Optimized and the SGM‑Consensus, suggests the variant is most likely 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 | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.823 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.229 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 0.0951 | 0.4175 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3463G>T | V1155L 2D AIThe SynGAP1 missense variant V1155L is not reported in ClinVar and has no gnomAD entry. Consensus from multiple in silico predictors shows a split: benign calls come from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM, while pathogenic calls arise from polyPhen‑2 (HumDiv and HumVar) and both AlphaMissense models. When predictions are grouped by agreement, the benign set includes five tools and the pathogenic set includes four. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized predicts pathogenicity, whereas the SGM‑Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans benign. No Foldetta stability data are available, so it does not influence the assessment. Overall, the preponderance of evidence, especially from the high‑accuracy AlphaMissense‑Optimized and the SGM‑Consensus, suggests the variant is most likely 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 | 0.750527 | Disordered | 0.855718 | Binding | 0.335 | 0.857 | 0.500 | -2.823 | Likely Benign | 0.956 | Likely Pathogenic | Likely Pathogenic | 0.229 | Likely Benign | -1.26 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.63 | Benign | 0.09 | Tolerated | 0.0951 | 0.4175 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3472G>A | V1158I 2D AIThe SynGAP1 missense variant V1158I is not 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 effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, FATHMM, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta 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. | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -3.504 | Likely Benign | 0.597 | Likely Pathogenic | Likely Benign | 0.129 | Likely Benign | -0.20 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.49 | Pathogenic | 0.07 | Tolerated | 0.0863 | 0.4180 | 4 | 3 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3472G>C | V1158L 2D AIThe SynGAP1 missense variant V1158L has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic, while the SGM‑Consensus remains Benign; Foldetta results are unavailable. Overall, the majority of evidence (five benign versus four pathogenic predictions, plus a benign consensus) points to a benign classification, and this does not contradict any ClinVar status because no ClinVar claim exists. Thus, 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. | Likely Benign | 0.599170 | Disordered | 0.877504 | Binding | 0.369 | 0.847 | 0.250 | -2.345 | Likely Benign | 0.964 | Likely Pathogenic | Likely Pathogenic | 0.187 | Likely Benign | -0.73 | Neutral | 0.992 | Probably Damaging | 0.989 | Probably Damaging | 2.78 | Benign | 0.56 | Tolerated | 0.1066 | 0.4642 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3475T>A | S1159T 2D AIThe SynGAP1 missense variant S1159T 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‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv and polyPhen‑2 HumVar. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. The variant is most likely benign, and this assessment does not contradict any ClinVar status because no ClinVar claim exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.626927 | Disordered | 0.867068 | Binding | 0.343 | 0.846 | 0.375 | -4.057 | Likely Benign | 0.207 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.59 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.68 | Benign | 0.28 | Tolerated | 0.1114 | 0.5715 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3493T>A | S1165T 2D AIThe SynGAP1 missense variant S1165T 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 predicts benign, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates Likely Benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of evidence points to a benign 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 | 0.509769 | Disordered | 0.835017 | Binding | 0.308 | 0.807 | 0.375 | -3.970 | Likely Benign | 0.572 | Likely Pathogenic | Likely Benign | 0.096 | Likely Benign | -0.85 | Neutral | 0.979 | Probably Damaging | 0.982 | Probably Damaging | 2.59 | Benign | 0.45 | Tolerated | 0.1660 | 0.5579 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3501C>A | D1167E 2D AIThe SynGAP1 missense variant D1167E 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, 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 because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -2.908 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.141 | Likely Benign | -1.19 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.57 | Benign | 0.24 | Tolerated | 0.1468 | 0.7368 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3501C>G | D1167E 2D AIThe SynGAP1 missense variant D1167E 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, 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 because no ClinVar assertion exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.599170 | Disordered | 0.783999 | Binding | 0.336 | 0.798 | 0.500 | -2.908 | Likely Benign | 0.940 | Likely Pathogenic | Ambiguous | 0.142 | Likely Benign | -1.19 | Neutral | 0.989 | Probably Damaging | 0.924 | Probably Damaging | 2.57 | Benign | 0.24 | Tolerated | 0.1468 | 0.7368 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.3509G>C | S1170T 2D AIThe SynGAP1 missense variant S1170T 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 not available. Overall, the majority of evidence points to a benign effect for S1170T, and this conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.622677 | Disordered | 0.719138 | Binding | 0.417 | 0.767 | 0.500 | -3.771 | Likely Benign | 0.163 | Likely Benign | Likely Benign | 0.338 | Likely Benign | -1.13 | Neutral | 0.992 | Probably Damaging | 0.925 | Probably Damaging | 5.37 | Benign | 0.08 | Tolerated | 0.1258 | 0.5897 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.350G>C | S117T 2D AIThe SynGAP1 missense variant S117T is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 HumVar, 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 SIFT 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 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 | 0.661982 | Disordered | 0.672422 | Binding | 0.357 | 0.877 | 0.625 | -4.602 | Likely Benign | 0.142 | Likely Benign | Likely Benign | 0.089 | Likely Benign | -0.98 | Neutral | 0.608 | Possibly Damaging | 0.092 | Benign | 3.79 | Benign | 0.02 | Affected | 0.1527 | 0.5505 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.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.3564T>A | D1188E 2D AIThe SynGAP1 missense variant D1188E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized model classifies the variant as pathogenic, whereas the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic interpretation. The variant is most likely pathogenic based on the consensus of computational tools, and this assessment does not contradict any ClinVar status, as none is currently assigned. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -2.517 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.382 | Likely Benign | -1.93 | Neutral | 0.992 | Probably Damaging | 0.992 | Probably Damaging | 5.50 | Benign | 0.00 | Affected | 0.0954 | 0.4616 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3564T>G | D1188E 2D AIThe SynGAP1 missense variant D1188E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy predictors give a mixed picture: AlphaMissense‑Optimized classifies the variant as pathogenic, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates a likely benign outcome, and Foldetta (combining FoldX‑MD and Rosetta outputs) has no available result for this residue. Overall, five of the nine evaluated tools predict pathogenicity while four predict benignity, with the high‑accuracy AlphaMissense‑Optimized result supporting the pathogenic prediction. Therefore, the variant is most likely pathogenic based on the current computational 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. | Likely Benign | Coiled-coil | 0.476583 | Structured | 0.484322 | Uncertain | 0.687 | 0.626 | 0.625 | -2.517 | Likely Benign | 0.960 | Likely Pathogenic | Likely Pathogenic | 0.382 | Likely Benign | -1.93 | Neutral | 0.992 | Probably Damaging | 0.992 | Probably Damaging | 5.50 | Benign | 0.00 | Affected | 0.0954 | 0.4616 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| 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.3579T>A | D1193E 2D AIThe SynGAP1 missense variant D1193E is predicted to be benign by the majority of in silico tools. Benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT classifies the change as pathogenic. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome. High‑accuracy assessments further support a benign effect: 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 absent from gnomAD, so there is no external evidence to contradict the computational predictions. Therefore, the variant is most likely benign, with no conflict with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | Coiled-coil | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | -3.788 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.307 | Likely Benign | -1.09 | Neutral | 0.008 | Benign | 0.028 | Benign | 5.47 | Benign | 0.00 | Affected | 0.1242 | 0.3957 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3579T>G | D1193E 2D AIThe SynGAP1 missense variant D1193E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while the only pathogenic prediction comes from SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments confirm this: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus likewise indicates a benign outcome. Foldetta results are not available, so they do not influence the assessment. Overall, the preponderance of evidence supports a benign classification for D1193E, 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 | 0.585406 | Disordered | 0.433390 | Uncertain | 0.807 | 0.600 | 0.375 | -3.788 | Likely Benign | 0.237 | Likely Benign | Likely Benign | 0.307 | Likely Benign | -1.09 | Neutral | 0.008 | Benign | 0.028 | Benign | 5.47 | Benign | 0.00 | Affected | 0.1242 | 0.3957 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| 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.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.35G>C | S12T 2D AIThe SynGAP1 missense variant S12T is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The high‑accuracy consensus, SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a benign effect. AlphaMissense‑Optimized independently scores the variant as 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 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 | 0.480142 | Structured | 0.490599 | Uncertain | 0.355 | 0.916 | 0.500 | -4.304 | Likely Benign | 0.117 | Likely Benign | Likely Benign | 0.075 | Likely Benign | -0.16 | Neutral | 0.208 | Benign | 0.024 | Benign | 4.14 | Benign | 0.00 | Affected | 0.1487 | 0.6303 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.3634T>A | S1212T 2D AIThe SynGAP1 missense variant S1212T is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive because it yields a 2‑to‑2 split. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts benign; SGM Consensus is unavailable; Foldetta, which combines FoldX‑MD and Rosetta stability calculations, has no reported output for this variant. Overall, the balance of evidence slightly favors a pathogenic interpretation, but the single high‑accuracy benign prediction and the lack of a consensus from SGM and Foldetta leave the assessment uncertain. There is no conflict with ClinVar status, as the variant has not been reported there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.566480 | Disordered | 0.548409 | Binding | 0.852 | 0.565 | 0.500 | -4.972 | Likely Benign | 0.759 | Likely Pathogenic | Likely Benign | 0.147 | Likely Benign | -2.19 | Neutral | 0.992 | Probably Damaging | 0.987 | Probably Damaging | 2.10 | Pathogenic | 0.00 | Affected | 0.0997 | 0.4618 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| 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.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.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.3768T>A | D1256E 2D AIThe SynGAP1 D1256E 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 and ESM1b, whereas the majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default all indicate pathogenicity. The SGM‑Consensus, which is a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as likely pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta results are unavailable. Taken together, the consensus of most evidence points to a pathogenic effect, and this conclusion does not contradict any existing ClinVar annotation (none is present). Thus, the variant is most likely pathogenic based on current predictive tools. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.549308 | Disordered | 0.445789 | Uncertain | 0.876 | 0.571 | 0.625 | -5.806 | Likely Benign | 0.842 | Likely Pathogenic | Ambiguous | 0.149 | Likely Benign | -2.71 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.72 | Pathogenic | 0.00 | Affected | 0.1022 | 0.4172 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3768T>G | D1256E 2D AIThe SynGAP1 D1256E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions come from REVEL and ESM1b, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and therefore reports the variant as likely pathogenic. AlphaMissense‑Optimized is uncertain, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta outputs) has no available result for this variant. Taken together, the majority of evidence points to a pathogenic effect, and this assessment does not contradict any ClinVar annotation because none exists. Thus, the variant is most likely pathogenic based on current predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | Coiled-coil | 0.549308 | Disordered | 0.445789 | Uncertain | 0.876 | 0.571 | 0.625 | -5.806 | Likely Benign | 0.842 | Likely Pathogenic | Ambiguous | 0.149 | Likely Benign | -2.71 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.72 | Pathogenic | 0.00 | Affected | 0.1022 | 0.4172 | 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.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.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.3805G>C | V1269L 2D AIThe SynGAP1 missense variant V1269L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. High‑accuracy assessments further support a deleterious outcome: AlphaMissense‑Optimized classifies the variant as pathogenic, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) reports it as Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence from both general and high‑accuracy 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 | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -3.572 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.299 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.0683 | 0.4082 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3805G>T | V1269L 2D AIThe SynGAP1 missense variant V1269L is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and ESM1b, whereas the majority of other in silico predictors (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) indicate a pathogenic impact. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus also indicates Likely Pathogenic. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of predictions 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 | 0.433034 | Structured | 0.787464 | Binding | 0.843 | 0.647 | 0.125 | -3.572 | Likely Benign | 0.971 | Likely Pathogenic | Likely Pathogenic | 0.299 | Likely Benign | -2.53 | Deleterious | 0.992 | Probably Damaging | 0.983 | Probably Damaging | 2.14 | Pathogenic | 0.00 | Affected | 0.0683 | 0.4082 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| c.3828C>A | D1276E 2D AIThe SynGAP1 missense variant D1276E is catalogued in gnomAD (ID 6‑33447876‑C‑A) but has no ClinVar submission. Functional prediction tools show a split assessment: benign calls come from REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, and AlphaMissense‑Optimized, whereas pathogenic calls arise from PROVEAN, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. A high‑accuracy consensus (SGM) that aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN yields a pathogenic verdict. AlphaMissense‑Optimized alone predicts benign, and no Foldetta stability data are available. Overall, the majority of individual predictors favor a benign effect, but the SGM consensus contradicts this by labeling the variant pathogenic. Because ClinVar contains no classification, there is no external evidence to resolve the discrepancy. Thus, based on the current computational evidence, the variant is most likely benign, though the SGM consensus suggests a possible pathogenic interpretation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | 6-33447876-C-A | -0.388 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.091 | Likely Benign | -2.64 | Deleterious | 0.027 | Benign | 0.020 | Benign | 1.26 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1027 | 0.5365 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.3828C>G | D1276E 2D AIThe SynGAP1 missense variant D1276E is not reported in ClinVar and is absent from gnomAD. Consensus from routine in silico predictors shows a split: benign calls from REVEL, polyPhen‑2 (HumDiv and HumVar), and ESM1b, versus pathogenic calls from PROVEAN, SIFT, and FATHMM; AlphaMissense‑Default remains uncertain. High‑accuracy assessments give a benign result from AlphaMissense‑Optimized, but the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—leans pathogenic. Foldetta, a protein‑folding stability method, has no available output for this residue. Overall, the balance of evidence tilts toward a benign interpretation, and this conclusion is not in conflict with the lack of ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.666105 | Disordered | 0.802156 | Binding | 0.636 | 0.705 | 0.625 | -0.388 | Likely Benign | 0.416 | Ambiguous | Likely Benign | 0.092 | Likely Benign | -2.64 | Deleterious | 0.027 | Benign | 0.020 | Benign | 1.26 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1027 | 0.5365 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||
| 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.3879C>A | D1293E 2D AIThe SynGAP1 missense variant D1293E is reported in gnomAD (variant ID 6‑33447927‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. In contrast, SIFT and FATHMM predict a pathogenic impact. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yields a “Likely Benign” verdict. High‑accuracy assessments further support benignity: 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 effect, 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 | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | 6-33447927-C-A | -2.627 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.042 | Likely Benign | -1.86 | Neutral | 0.011 | Benign | 0.008 | Benign | 2.39 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1512 | 0.3425 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.3879C>G | D1293E 2D AIThe SynGAP1 missense variant D1293E is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports 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 D1293E, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.779859 | Disordered | 0.892346 | Binding | 0.569 | 0.801 | 0.625 | -2.627 | Likely Benign | 0.136 | Likely Benign | Likely Benign | 0.041 | Likely Benign | -1.86 | Neutral | 0.011 | Benign | 0.008 | Benign | 2.39 | Pathogenic | 0.00 | Affected | 3.77 | 5 | 0.1512 | 0.3425 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| 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.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.392G>C | G131A 2D AIThe SynGAP1 missense variant G131A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, and SIFT. AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts benign. Foldetta results are unavailable. Overall, the majority of evidence (5 benign vs 3 pathogenic) supports a benign classification. 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. | 0.429200 | Structured | 0.724779 | Binding | 0.302 | 0.891 | 0.250 | -4.891 | Likely Benign | 0.512 | Ambiguous | Likely Benign | 0.138 | Likely Benign | -2.96 | Deleterious | 0.620 | Possibly Damaging | 0.157 | Benign | 3.99 | Benign | 0.01 | Affected | 0.3981 | 0.4814 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.3950G>C | G1317A 2D AIThe SynGAP1 missense variant G1317A is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN and SIFT. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion is consistent with the lack of ClinVar annotation. Thus, the variant is most likely benign and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.908098 | Disordered | 0.971158 | Binding | 0.385 | 0.879 | 0.750 | -3.761 | Likely Benign | 0.190 | Likely Benign | Likely Benign | 0.049 | Likely Benign | -2.62 | Deleterious | 0.001 | Benign | 0.002 | Benign | 4.08 | Benign | 0.00 | Affected | 0.3582 | 0.4284 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.4004G>C | G1335A 2D AIThe SynGAP1 missense variant G1335A is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL and ESM1b, whereas the remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized is pathogenic, and the SGM Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is also likely pathogenic. Foldetta, a protein‑folding stability method, has no available result for this variant. Overall, the preponderance of evidence points to a pathogenic effect for G1335A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.891961 | Disordered | 0.967705 | Binding | 0.323 | 0.724 | 0.750 | -4.942 | Likely Benign | 0.993 | Likely Pathogenic | Likely Pathogenic | 0.357 | Likely Benign | -3.69 | Deleterious | 0.996 | Probably Damaging | 0.992 | Probably Damaging | 2.05 | Pathogenic | 0.00 | Affected | 0.3383 | 0.4953 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.401G>C | S134T 2D AIThe SynGAP1 missense variant S134T is listed in gnomAD (ID 6‑33432698‑G‑C) but has no ClinVar entry. Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also favors benign. Foldetta, a protein‑folding stability method combining FoldX‑MD and Rosetta outputs, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact; this conclusion is not contradicted by ClinVar, which contains no classification for S134T. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.447574 | Structured | 0.695837 | Binding | 0.333 | 0.898 | 0.250 | 6-33432698-G-C | 1 | 6.32e-7 | -5.187 | Likely Benign | 0.563 | Ambiguous | Likely Benign | 0.069 | Likely Benign | -1.76 | Neutral | 0.034 | Benign | 0.047 | Benign | 3.85 | Benign | 0.00 | Affected | 3.61 | 5 | 0.1083 | 0.5326 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.4026C>A | D1342E 2D AIThe SynGAP1 missense variant D1342E is catalogued in gnomAD (ID 6‑33451900‑C‑A) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all report benign or tolerated outcomes. Only SIFT predicts 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 this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is Likely Benign; Foldetta results are unavailable. Overall, the preponderance of evidence indicates that D1342E 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 | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | 6-33451900-C-A | -3.169 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.88 | Neutral | 0.225 | Benign | 0.084 | Benign | 4.16 | Benign | 0.04 | Affected | 4.32 | 4 | 0.2130 | 0.5720 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.4026C>G | D1342E 2D AIThe SynGAP1 missense variant D1342E is not reported in ClinVar and is absent from gnomAD. Prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign, while only SIFT predicts it as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) is likely benign. Foldetta results are unavailable, so they do not influence the assessment. Overall, the consensus of available predictions points to a benign effect for D1342E, 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 | 0.921076 | Disordered | 0.981682 | Binding | 0.316 | 0.678 | 0.875 | -3.169 | Likely Benign | 0.134 | Likely Benign | Likely Benign | 0.026 | Likely Benign | -0.88 | Neutral | 0.225 | Benign | 0.084 | Benign | 4.16 | Benign | 0.04 | Affected | 4.32 | 4 | 0.2130 | 0.5720 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| 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.418T>A | S140T 2D AIThe SynGAP1 missense variant S140T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, 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, whereas the SGM‑Consensus (majority vote) remains Likely Benign. Foldetta predictions are unavailable. Overall, the balance of evidence, particularly the SGM‑Consensus and the majority of benign‑predicting tools, suggests that the variant is most likely benign. 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 | 0.476583 | Structured | 0.587898 | Binding | 0.321 | 0.896 | 0.625 | -6.336 | Likely Benign | 0.873 | Likely Pathogenic | Ambiguous | 0.132 | Likely Benign | -1.94 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.59 | Benign | 0.03 | Affected | 0.1069 | 0.5722 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.436T>A | S146T 2D AIThe SynGAP1 missense variant S146T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a tie (two pathogenic, two benign) and thus unavailable; Foldetta results are not provided. Overall, the majority of evidence (five benign vs. three pathogenic) supports a benign classification. 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. | 0.541878 | Disordered | 0.508612 | Binding | 0.349 | 0.837 | 0.625 | -9.795 | Likely Pathogenic | 0.786 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | -2.09 | Neutral | 0.084 | Benign | 0.042 | Benign | 3.65 | Benign | 0.00 | Affected | 0.1267 | 0.5075 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| 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.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.464G>C | S155T 2D AIThe SynGAP1 missense variant S155T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b; AlphaMissense‑Default 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 majority of reliable predictors and the consensus analysis indicate that S155T is most likely benign, and this conclusion does not contradict any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.497853 | Structured | 0.515359 | Binding | 0.292 | 0.787 | 0.500 | -8.635 | Likely Pathogenic | 0.523 | Ambiguous | Likely Benign | 0.153 | Likely Benign | -1.60 | Neutral | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 3.84 | Benign | 0.00 | Affected | 0.1151 | 0.5694 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.494G>C | S165T 2D AIThe SynGAP1 missense variant S165T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, 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 | 0.429200 | Structured | 0.509123 | Binding | 0.324 | 0.644 | 0.250 | -6.952 | Likely Benign | 0.205 | Likely Benign | Likely Benign | 0.076 | Likely Benign | -0.94 | Neutral | 0.155 | Benign | 0.064 | Benign | 4.02 | Benign | 0.00 | Affected | 0.1754 | 0.5779 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.49T>A | S17T 2D AIThe SynGAP1 missense variant S17T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect. The variant is most likely benign, 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 | 0.483068 | Structured | 0.452228 | Uncertain | 0.341 | 0.910 | 0.375 | -3.782 | Likely Benign | 0.197 | Likely Benign | Likely Benign | 0.061 | Likely Benign | -0.58 | Neutral | 0.052 | Benign | 0.004 | Benign | 4.10 | Benign | 0.00 | Affected | 0.1667 | 0.6933 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.501C>A | D167E 2D AIThe SynGAP1 D167E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it receives two benign votes and two uncertain votes, yielding no clear majority. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -7.636 | In-Between | 0.516 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.52 | Neutral | 0.063 | Benign | 0.062 | Benign | 4.07 | Benign | 0.00 | Affected | 0.1392 | 0.7144 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.501C>G | D167E 2D AIThe SynGAP1 D167E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while ESM1b and AlphaMissense‑Default are uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive because it receives two benign votes and two uncertain votes, yielding no clear majority. Foldetta, which would provide a protein‑folding stability estimate, has no available result for this variant. Overall, the preponderance of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.429200 | Structured | 0.502306 | Binding | 0.377 | 0.667 | 0.375 | -7.636 | In-Between | 0.516 | Ambiguous | Likely Benign | 0.067 | Likely Benign | -1.52 | Neutral | 0.063 | Benign | 0.062 | Benign | 4.07 | Benign | 0.00 | Affected | 0.1392 | 0.7144 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.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.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.538T>A | S180T 2D AIThe SynGAP1 missense variant S180T is not 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, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive (2 pathogenic vs. 2 benign). Foldetta results are unavailable. Overall, the majority of predictions (six benign vs. three pathogenic) support a benign classification. This consensus does not contradict any ClinVar status, as no ClinVar entry exists for this variant. Thus, the variant is most likely benign based on current predictive evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.509769 | Disordered | 0.442877 | Uncertain | 0.320 | 0.616 | 0.500 | -9.851 | Likely Pathogenic | 0.669 | Likely Pathogenic | Likely Benign | 0.114 | Likely Benign | -2.07 | Neutral | 0.057 | Benign | 0.020 | Benign | 3.86 | Benign | 0.02 | Affected | 0.1238 | 0.5171 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.544T>A | S182T 2D AIThe SynGAP1 missense variant S182T is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect are SIFT, ESM1b, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is a 2‑vs‑2 tie, and Foldetta results are unavailable. Overall, the majority of available predictions (five benign vs three pathogenic) suggest a benign impact. This consensus does not contradict any ClinVar annotation, as no ClinVar entry exists for this variant. Thus, based on current computational evidence, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.501700 | Disordered | 0.436016 | Uncertain | 0.368 | 0.619 | 0.625 | -11.247 | Likely Pathogenic | 0.857 | Likely Pathogenic | Ambiguous | 0.128 | Likely Benign | -2.29 | Neutral | 0.231 | Benign | 0.081 | Benign | 3.68 | Benign | 0.00 | Affected | 0.1624 | 0.5657 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||||||
| c.553T>A | S185T 2D AIThe SynGAP1 missense variant S185T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that indicate a benign effect include REVEL, polyPhen‑2 HumVar, and FATHMM. Tools that predict a pathogenic effect include PROVEAN, polyPhen‑2 HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, while Foldetta (combining FoldX‑MD and Rosetta outputs) is not available for this variant. Overall, the majority of evidence points to a pathogenic impact. The variant is most likely pathogenic, and this assessment does not contradict any existing ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.545602 | Disordered | 0.430485 | Uncertain | 0.365 | 0.623 | 0.500 | -10.943 | Likely Pathogenic | 0.903 | Likely Pathogenic | Ambiguous | 0.186 | Likely Benign | -2.54 | Deleterious | 0.596 | Possibly Damaging | 0.142 | Benign | 3.60 | Benign | 0.00 | Affected | 0.1484 | 0.6236 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.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.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.572G>C | S191T 2D AIThe SynGAP1 missense variant S191T is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools overwhelmingly indicate a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all score benign, while the majority‑vote SGM‑Consensus also classifies it as likely benign. Only SIFT predicts a pathogenic outcome, and ESM1b remains uncertain. High‑accuracy assessments corroborate the benign consensus: AlphaMissense‑Optimized returns a benign prediction and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also reports likely benign. Foldetta stability analysis is not available for this variant. Overall, the preponderance of evidence supports a benign classification, 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 | 0.429200 | Structured | 0.428475 | Uncertain | 0.322 | 0.615 | 0.125 | -7.315 | In-Between | 0.319 | Likely Benign | Likely Benign | 0.150 | Likely Benign | -2.34 | Neutral | 0.231 | Benign | 0.081 | Benign | 3.81 | Benign | 0.03 | Affected | 0.1466 | 0.7405 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.5G>C | S2T 2D AIThe SynGAP1 missense variant S2T is reported in gnomAD (variant ID 6‑33420269‑G‑C) but has no ClinVar entry. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the change as benign. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely benign effect. High‑accuracy assessments confirm this: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the preponderance of evidence points to a benign impact for S2T, and this conclusion is consistent with the absence of a ClinVar pathogenic classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.671169 | Disordered | 0.543646 | Binding | 0.382 | 0.922 | 0.750 | 6-33420269-G-C | -4.443 | Likely Benign | 0.144 | Likely Benign | Likely Benign | 0.051 | Likely Benign | -0.55 | Neutral | 0.052 | Benign | 0.004 | Benign | 4.09 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1575 | 0.6954 | 1 | 1 | 0.1 | 14.03 | ||||||||||||||||||||||||||||||||||||
| c.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.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.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.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.634T>A | S212T 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant S212T is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include FoldX and FATHMM, whereas the majority of tools predict a pathogenic impact: REVEL, SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus (derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. With most evidence pointing to deleterious effects and no conflicting ClinVar annotation, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.158265 | Structured | 0.381517 | Uncertain | 0.846 | 0.278 | 0.125 | -11.473 | Likely Pathogenic | 0.939 | Likely Pathogenic | Ambiguous | 0.32 | Likely Benign | 0.2 | 2.03 | Destabilizing | 1.18 | Ambiguous | 0.58 | Ambiguous | 0.767 | Likely Pathogenic | -2.58 | Deleterious | 0.956 | Probably Damaging | 0.931 | Probably Damaging | 5.79 | Benign | 0.01 | Affected | 0.1077 | 0.6284 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.644G>C | G215A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G215A is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a pathogenic effect include SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The only tool predicting a benign outcome is FATHMM. Predictions that are uncertain or inconclusive are Foldetta, Rosetta, and premPS. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta is uncertain. Overall, the majority of evidence indicates that G215A is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.155435 | Structured | 0.382818 | Uncertain | 0.791 | 0.291 | 0.000 | -8.930 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.36 | Destabilizing | 0.2 | 1.35 | Ambiguous | 1.86 | Ambiguous | 0.59 | Ambiguous | 0.874 | Likely Pathogenic | -5.08 | Deleterious | 0.999 | Probably Damaging | 0.995 | Probably Damaging | 5.61 | Benign | 0.02 | Affected | 0.3897 | 0.5525 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||
| 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.664G>C | V222L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222L 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, FATHMM, and Foldetta, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—also predicts pathogenic; Foldetta, a protein‑folding stability method, predicts benign. Overall, the majority of evidence (seven pathogenic vs. four benign) points to a pathogenic effect. The variant’s predicted pathogenicity is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -7.626 | In-Between | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.00 | Likely Benign | 0.3 | 0.06 | Likely Benign | 0.03 | Likely Benign | 0.60 | Ambiguous | 0.617 | Likely Pathogenic | -2.59 | Deleterious | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.49 | Benign | 0.05 | Affected | 0.0863 | 0.4349 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.664G>T | V222L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V222L 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, FATHMM, and Foldetta, whereas those that agree on a pathogenic effect are REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and ESM1b) give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus—derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (uncertain), FATHMM (benign), and PROVEAN (pathogenic)—also predicts pathogenic; Foldetta, a protein‑folding stability method, predicts benign. Overall, the majority of evidence (seven pathogenic vs. four benign) points to a pathogenic effect. The variant’s predicted pathogenicity is not contradicted by any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.116183 | Structured | 0.402706 | Uncertain | 0.885 | 0.310 | 0.125 | -7.626 | In-Between | 0.987 | Likely Pathogenic | Likely Pathogenic | 0.00 | Likely Benign | 0.3 | 0.06 | Likely Benign | 0.03 | Likely Benign | 0.60 | Ambiguous | 0.617 | Likely Pathogenic | -2.59 | Deleterious | 0.984 | Probably Damaging | 0.956 | Probably Damaging | 5.49 | Benign | 0.05 | Affected | 0.0863 | 0.4349 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| 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.676T>A | S226T 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant S226T is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome, while FoldX is uncertain and therefore 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) indicates likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts benign. Based on the preponderance of evidence, the variant is most likely benign, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.129801 | Structured | 0.334959 | Uncertain | 0.800 | 0.324 | 0.250 | -5.066 | Likely Benign | 0.102 | Likely Benign | Likely Benign | 0.53 | Ambiguous | 0.2 | 0.12 | Likely Benign | 0.33 | Likely Benign | -0.10 | Likely Benign | 0.326 | Likely Benign | -1.47 | Neutral | 0.390 | Benign | 0.079 | Benign | 5.75 | Benign | 0.05 | Affected | 0.1991 | 0.6681 | 1 | 1 | 0.1 | 14.03 | |||||||||||||||||||||||||||||
| c.680G>C | G227A 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant G227A is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM. Those that agree on a pathogenic effect are REVEL, FoldX, Rosetta, Foldetta, PROVEAN, SIFT, and AlphaMissense‑Default. Predictions that remain uncertain are premPS, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) yields a pathogenic majority, and Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, also predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overall consensus of the majority of tools and the high‑accuracy 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. | PH | 0.106997 | Structured | 0.329995 | Uncertain | 0.800 | 0.329 | 0.250 | -7.344 | In-Between | 0.920 | Likely Pathogenic | Ambiguous | 2.45 | Destabilizing | 0.4 | 5.14 | Destabilizing | 3.80 | Destabilizing | 0.78 | Ambiguous | 0.682 | Likely Pathogenic | -5.08 | Deleterious | 0.097 | Benign | 0.023 | Benign | 5.71 | Benign | 0.04 | Affected | 0.3987 | 0.5221 | 1 | 0 | 2.2 | 14.03 | ||||||||||||||||||||||||||||||
| c.69T>A | D23E 2D AIThe SynGAP1 D23E missense variant is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a Likely Benign classification. High‑accuracy assessments show AlphaMissense‑Optimized as Benign and the SGM‑Consensus as Likely Benign; Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact. This conclusion is not contradicted by ClinVar, as no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | -3.329 | Likely Benign | 0.565 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -1.35 | Neutral | 0.643 | Possibly Damaging | 0.417 | Benign | 3.59 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2420 | 0.8363 | 2 | 3 | 0.0 | 14.03 | |||||||||||||||||||||||||||||||||||||
| c.69T>G | D23E 2D AIThe SynGAP1 missense variant D23E is listed in gnomAD (ID 6‑33423478‑T‑G) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions arise from polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts benign, and the SGM‑Consensus (majority vote) also indicates benign. No Foldetta stability analysis is available for this variant. Overall, the majority of evidence—including the consensus and high‑accuracy tools—points to a benign effect, and this conclusion is not contradicted by any ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.557691 | Disordered | 0.440341 | Uncertain | 0.369 | 0.892 | 0.375 | 6-33423478-T-G | 15 | 9.29e-6 | -3.329 | Likely Benign | 0.565 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -1.35 | Neutral | 0.643 | Possibly Damaging | 0.417 | Benign | 3.59 | Benign | 0.00 | Affected | 4.32 | 1 | 0.2420 | 0.8363 | 2 | 3 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||||||
| c.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.70G>A | V24I 2D AIThe SynGAP1 missense variant V24I is listed in ClinVar with an “Uncertain” status and is present in gnomAD (variant ID 6-33423479-G-A). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta results are not available. Taken together, the overwhelming majority of computational evidence supports a benign impact for V24I, and this conclusion does not contradict the ClinVar designation, which remains uncertain. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | Uncertain | 1 | 6-33423479-G-A | 9 | 5.58e-6 | -3.701 | Likely Benign | 0.137 | Likely Benign | Likely Benign | 0.069 | Likely Benign | -0.25 | Neutral | 0.043 | Benign | 0.031 | Benign | 3.96 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0844 | 0.4564 | 3 | 4 | 0.3 | 14.03 | ||||||||||||||||||||||||||||||||
| c.70G>C | V24L 2D AIThe SynGAP1 missense variant V24L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.590 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.62 | Neutral | 0.043 | Benign | 0.011 | Benign | 3.94 | Benign | 0.00 | Affected | 0.1102 | 0.5226 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.70G>T | V24L 2D AIThe SynGAP1 missense variant V24L is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Only SIFT predicts a pathogenic outcome. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a “Likely Benign” classification. High‑accuracy assessments further support a benign interpretation: AlphaMissense‑Optimized is benign, and the SGM‑Consensus is likely benign; Foldetta results are not available. Overall, the majority of evidence points to a benign effect for V24L, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.541878 | Disordered | 0.438970 | Uncertain | 0.382 | 0.890 | 0.500 | -2.590 | Likely Benign | 0.320 | Likely Benign | Likely Benign | 0.053 | Likely Benign | -0.62 | Neutral | 0.043 | Benign | 0.011 | Benign | 3.94 | Benign | 0.00 | Affected | 0.1102 | 0.5226 | 2 | 1 | -0.4 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.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.748G>A | V250I 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant V250I is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). All evaluated in silico predictors classify the change as benign: REVEL, FoldX, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). The high‑accuracy tools likewise predict a benign effect: AlphaMissense‑Optimized is benign, the SGM Consensus is “Likely Benign,” and Foldetta (combining FoldX‑MD and Rosetta outputs) is benign. No pathogenic predictions are present. Therefore, based on the available computational evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -6.696 | Likely Benign | 0.085 | Likely Benign | Likely Benign | -0.44 | Likely Benign | 0.1 | -0.01 | Likely Benign | -0.23 | Likely Benign | 0.35 | Likely Benign | 0.362 | Likely Benign | -0.79 | Neutral | 0.384 | Benign | 0.070 | Benign | 6.09 | Benign | 0.13 | Tolerated | 0.0571 | 0.3644 | 4 | 3 | 0.3 | 14.03 | |||||||||||||||||||||||||||||
| c.748G>C | V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.649 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | -0.23 | Likely Benign | 0.1 | 2.47 | Destabilizing | 1.12 | Ambiguous | 0.66 | Ambiguous | 0.690 | Likely Pathogenic | -2.47 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 5.81 | Benign | 0.04 | Affected | 0.0698 | 0.4229 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.748G>T | V250L 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 V250L variant is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that classify the variant as benign include FoldX, PROVEAN, FATHMM, AlphaMissense‑Optimized, and polyPhen2_HumVar. Those that predict pathogenicity are REVEL, polyPhen2_HumDiv, SIFT, ESM1b, and AlphaMissense‑Default. Tools with inconclusive results—Foldetta and premPS—are noted as uncertain. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is ambiguous (two pathogenic vs. two benign votes), and Foldetta remains uncertain. Overall, the majority of predictions (five pathogenic vs. four benign) lean toward a pathogenic effect, and this conclusion does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | PH | 0.447574 | Structured | 0.244075 | Uncertain | 0.778 | 0.324 | 0.125 | -11.649 | Likely Pathogenic | 0.587 | Likely Pathogenic | Likely Benign | -0.23 | Likely Benign | 0.1 | 2.47 | Destabilizing | 1.12 | Ambiguous | 0.66 | Ambiguous | 0.690 | Likely Pathogenic | -2.47 | Neutral | 0.767 | Possibly Damaging | 0.344 | Benign | 5.81 | Benign | 0.04 | Affected | 0.0698 | 0.4229 | 2 | 1 | -0.4 | 14.03 | ||||||||||||||||||||||||||||||
| c.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.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.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.77G>C | G26A 2D AIThe SynGAP1 missense variant G26A is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) which classifies the variant as Likely Benign. In contrast, polyPhen‑2 (HumDiv and HumVar) and SIFT all predict a pathogenic impact. High‑accuracy assessments further support a benign outcome: AlphaMissense‑Optimized predicts Benign, and the SGM‑Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Benign. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the majority of evidence points to a benign effect for G26A, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.486429 | Structured | 0.438291 | Uncertain | 0.351 | 0.878 | 0.375 | -3.308 | Likely Benign | 0.135 | Likely Benign | Likely Benign | 0.062 | Likely Benign | -1.25 | Neutral | 0.953 | Possibly Damaging | 0.952 | Probably Damaging | 4.02 | Benign | 0.00 | Affected | 0.4093 | 0.5251 | 1 | 0 | 2.2 | 14.03 | |||||||||||||||||||||||||||||||||||||||
| c.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.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.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.861T>A | D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -5.250 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.35 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.50 | Likely Benign | 0.416 | Likely Benign | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.1541 | 0.7833 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.861T>G | D287E 2D 3DClick to see structure in 3D Viewer AISynGAP1 D287E is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, premPS, ESM1b, and the protein‑folding stability method Foldetta; pathogenic predictions arise from SGM‑Consensus, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy AlphaMissense‑Optimized tool classifies the variant as pathogenic. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default (pathogenic), ESM1b (benign), FATHMM (pathogenic), and PROVEAN (pathogenic), also reports it as pathogenic. In contrast, Foldetta, which integrates FoldX‑MD and Rosetta outputs, predicts a benign effect on protein stability. No evidence is available from Rosetta alone. Overall, the majority of predictions, including the high‑accuracy methods, indicate a pathogenic effect, and this assessment does not contradict the absence of a ClinVar classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.102787 | Structured | 0.389029 | Uncertain | 0.912 | 0.268 | 0.000 | -5.250 | Likely Benign | 0.990 | Likely Pathogenic | Likely Pathogenic | 0.35 | Likely Benign | 0.2 | 0.54 | Ambiguous | 0.45 | Likely Benign | 0.50 | Likely Benign | 0.416 | Likely Benign | -3.68 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.54 | Pathogenic | 0.01 | Affected | 0.1541 | 0.7833 | 3 | 2 | 0.0 | 14.03 | |||||||||||||||||||||||||||||
| c.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.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.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.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.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.912C>A | D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant has no ClinVar entry and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, and the SGM Consensus (derived from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split. Overall, the majority of evidence supports a benign effect, and this conclusion does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.715 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.28 | Likely Benign | 0.48 | Likely Benign | 0.186 | Likely Benign | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.77 | Pathogenic | 0.04 | Affected | 0.1504 | 0.6998 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.912C>G | D304E 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 D304E missense variant is not reported in ClinVar and is absent from gnomAD. Functional prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, Foldetta, premPS, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Tools that predict a pathogenic outcome are PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign, Foldetta as benign, while the SGM Consensus—derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—yields a tie and is therefore inconclusive. Overall, the balance of evidence favors a benign classification, and this conclusion does not conflict with the absence of a ClinVar assertion. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.352862 | Structured | 0.285053 | Uncertain | 0.764 | 0.271 | 0.250 | -2.715 | Likely Benign | 0.233 | Likely Benign | Likely Benign | 0.34 | Likely Benign | 0.1 | 0.21 | Likely Benign | 0.28 | Likely Benign | 0.48 | Likely Benign | 0.186 | Likely Benign | -3.29 | Deleterious | 0.997 | Probably Damaging | 0.994 | Probably Damaging | 1.77 | Pathogenic | 0.04 | Affected | 0.1504 | 0.6998 | 3 | 2 | 0.0 | 14.03 | ||||||||||||||||||||||||||||||
| c.916G>A | V306I 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant V306I is listed in ClinVar with an uncertain significance (ClinVar ID 4708871) and is present in gnomAD (ID 6‑33437821‑G‑A). Functional prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM‑Consensus, and Rosetta. Tools that predict a pathogenic outcome are PolyPhen‑2 HumDiv, PolyPhen‑2 HumVar, and FATHMM. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates a likely benign effect; Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, reports an uncertain result and is therefore not considered evidence for or against pathogenicity. Overall, the majority of predictions support a benign classification, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | C2 | 0.363090 | Structured | 0.315026 | Uncertain | 0.896 | 0.287 | 0.125 | Conflicting | 2 | 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.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.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 (gnomAD ID 6‑33437863‑G‑C) is listed in ClinVar as uncertain. Functional prediction tools show a predominance of benign calls: REVEL, FoldX, PROVEAN, polyPhen2_HumVar, SIFT, ESM1b, and AlphaMissense‑Optimized all predict benign. Pathogenic predictions come from polyPhen2_HumDiv and FATHMM. The remaining tools—Rosetta, Foldetta, premPS, and AlphaMissense‑Default—return uncertain results. 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; Foldetta, which integrates FoldX‑MD and Rosetta outputs, remains uncertain. Overall, the balance of evidence favors a benign effect for V320L, which is consistent with its ClinVar designation of uncertain significance rather than a pathogenic classification. Based on the aggregate predictions, V320L is most likely benign, which does not contradict its ClinVar status of uncertain significance. 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 | Conflicting | 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.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.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.1278C>A | N426K 2D  3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N426K resides in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Rosetta, SIFT, and FATHMM. Those that predict a pathogenic effect are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools give inconclusive results: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect. Overall, the majority of predictions lean toward pathogenicity, and this conclusion does not contradict the ClinVar status, which is currently unclassified. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -11.659 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | 0.00 | Likely Benign | 0.02 | Likely Benign | 0.54 | Ambiguous | 0.197 | Likely Benign | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.978 | Probably Damaging | 3.38 | Benign | 0.12 | Tolerated | 0.1906 | 0.2822 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1278C>G | N426K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N426K is located in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that classify the variant as benign include REVEL, FoldX, Rosetta, SIFT, and FATHMM, while those that predict pathogenicity are SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. Two tools report uncertainty: AlphaMissense‑Optimized and premPS. High‑accuracy assessments show that AlphaMissense‑Optimized is uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts a benign effect on protein stability. Overall, the majority of predictions lean toward pathogenicity, with a split in the most reliable methods. Therefore, the variant is most likely pathogenic based on the current computational evidence, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.394941 | Uncertain | 0.959 | 0.287 | 0.000 | -11.659 | Likely Pathogenic | 0.867 | Likely Pathogenic | Ambiguous | 0.03 | Likely Benign | 0.0 | 0.00 | Likely Benign | 0.02 | Likely Benign | 0.54 | Ambiguous | 0.197 | Likely Benign | -3.86 | Deleterious | 0.998 | Probably Damaging | 0.978 | Probably Damaging | 3.38 | Benign | 0.12 | Tolerated | 0.1906 | 0.2822 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1320T>A | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | 0.058 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 0.1660 | 0.2550 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.1320T>G | N440K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N440K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and FATHMM. Tools that predict a pathogenic effect are ESM1b and AlphaMissense‑Default. The remaining methods—FoldX, Rosetta, Foldetta, and AlphaMissense‑Optimized—yield uncertain or inconclusive results and are treated as unavailable. High‑accuracy assessments are likewise inconclusive: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑vs‑2 tie, and Foldetta is uncertain. Based on the overall distribution of predictions, the variant is most likely benign, and this assessment does not contradict the ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.191378 | Structured | 0.267204 | Uncertain | 0.929 | 0.245 | 0.000 | -10.114 | Likely Pathogenic | 0.895 | Likely Pathogenic | Ambiguous | 0.92 | Ambiguous | 0.1 | 1.04 | Ambiguous | 0.98 | Ambiguous | 0.40 | Likely Benign | 0.057 | Likely Benign | -1.97 | Neutral | 0.206 | Benign | 0.021 | Benign | 3.50 | Benign | 0.19 | Tolerated | 0.1660 | 0.2550 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.135C>A | N45K 2D AISynGAP1 missense variant N45K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome; Foldetta results are unavailable. Overall, the balance of evidence—five benign versus four pathogenic predictions, with two high‑accuracy tools supporting benign—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -1.711 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -0.58 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.2409 | 0.6724 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.135C>G | N45K 2D AISynGAP1 missense variant N45K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign, and the SGM‑Consensus (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates a benign outcome; Foldetta results are unavailable. Overall, the balance of evidence—five benign versus four pathogenic predictions, with two high‑accuracy tools supporting benign—suggests that the variant is most likely benign. This conclusion does not contradict ClinVar status, as no ClinVar classification exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.401658 | Structured | 0.431853 | Uncertain | 0.498 | 0.741 | 0.375 | -1.711 | Likely Benign | 0.697 | Likely Pathogenic | Likely Benign | 0.082 | Likely Benign | -0.58 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.13 | Benign | 0.00 | Affected | 0.2409 | 0.6724 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.1461C>A | N487K 2D AIThe SynGAP1 missense variant N487K lies in the GAP domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM. The remaining tools—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact, and the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is labeled “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. No other stability predictions are available. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict the ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | 0.489 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1953 | 0.2721 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1461C>G | N487K 2D AIThe SynGAP1 missense variant N487K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely disagree: benign predictions come from REVEL and FATHMM, while pathogenic predictions are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Stability‑related methods (FoldX, Rosetta, premPS, Foldetta) yield uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as unavailable. Overall, the majority of evidence points to a pathogenic effect, and this conclusion does not contradict any ClinVar annotation (none is available). Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.209395 | Structured | 0.338511 | Uncertain | 0.890 | 0.243 | 0.125 | -13.520 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 1.10 | Ambiguous | 0.9 | 1.28 | Ambiguous | 1.19 | Ambiguous | 0.80 | Ambiguous | 0.488 | Likely Benign | -5.97 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.72 | Benign | 0.01 | Affected | 0.1953 | 0.2721 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1569C>A | N523K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523K is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain results are reported only by Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence supports a pathogenic classification for this variant, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -12.276 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.17 | Likely Benign | 0.2 | -0.58 | Ambiguous | -0.38 | Likely Benign | 0.73 | Ambiguous | 0.607 | Likely Pathogenic | -5.35 | Deleterious | 0.972 | Probably Damaging | 0.728 | Possibly Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.1837 | 0.2866 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1569C>G | N523K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N523K is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include FoldX and Foldetta, whereas the majority of tools (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome. Uncertain results are reported only by Rosetta and premPS. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta as benign. Taken together, the preponderance of evidence supports a pathogenic classification for this variant, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.069024 | Structured | 0.033426 | Uncertain | 0.883 | 0.383 | 0.125 | -12.276 | Likely Pathogenic | 0.983 | Likely Pathogenic | Likely Pathogenic | -0.17 | Likely Benign | 0.2 | -0.58 | Ambiguous | -0.38 | Likely Benign | 0.73 | Ambiguous | 0.607 | Likely Pathogenic | -5.35 | Deleterious | 0.972 | Probably Damaging | 0.728 | Possibly Damaging | -1.30 | Pathogenic | 0.04 | Affected | 0.1837 | 0.2866 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1626C>A | N542K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542K is not reported in ClinVar and has no entries in gnomAD. Prediction tools largely disagree: benign calls come from FoldX, SIFT, and Foldetta; pathogenic calls come from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (Rosetta and premPS) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also predicts pathogenic, whereas Foldetta predicts benign. No prediction or stability result is missing or inconclusive. Overall, the majority of evidence (nine pathogenic vs three benign) points to a pathogenic effect. This conclusion is not contradicted by ClinVar status, which has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -11.967 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.36 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.09 | Likely Benign | 0.75 | Ambiguous | 0.610 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.23 | Pathogenic | 0.10 | Tolerated | 0.1870 | 0.4349 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1626C>G | N542K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N542K 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 FoldX, SIFT, and Foldetta. Those that predict a pathogenic effect are SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (Rosetta and premPS) returned uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also pathogenic, while Foldetta predicts benign stability. No prediction or folding result is missing or inconclusive. Overall, the majority of evidence (nine pathogenic vs. three benign) indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.053060 | Structured | 0.026143 | Uncertain | 0.953 | 0.331 | 0.000 | -11.967 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.36 | Likely Benign | 0.1 | 0.53 | Ambiguous | 0.09 | Likely Benign | 0.75 | Ambiguous | 0.610 | Likely Pathogenic | -5.33 | Deleterious | 1.000 | Probably Damaging | 0.997 | Probably Damaging | -1.23 | Pathogenic | 0.10 | Tolerated | 0.1870 | 0.4349 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.162C>A | N54K 2D AIThe SynGAP1 missense variant N54K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign) and is treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic. 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. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -8.252 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -0.82 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 0.2010 | 0.5987 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.162C>G | N54K 2D AIThe SynGAP1 missense variant N54K is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is inconclusive (2 pathogenic vs. 2 benign) and is treated as unavailable. High‑accuracy methods show AlphaMissense‑Optimized as benign; Foldetta results are not provided, so its stability prediction is unavailable. Overall, the balance of evidence (five pathogenic vs. four benign predictions) suggests the variant is most likely pathogenic. 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. | 0.196879 | Structured | 0.464669 | Uncertain | 0.504 | 0.659 | 0.000 | -8.252 | Likely Pathogenic | 0.779 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -0.82 | Neutral | 0.659 | Possibly Damaging | 0.775 | Possibly Damaging | 4.23 | Benign | 0.00 | Affected | 0.2010 | 0.5987 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.1668C>A | N556K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, premPS, and SIFT, whereas the remaining tools (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized) predict it to be pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of predictions support a pathogenic effect, and this conclusion is not contradicted by any ClinVar annotation. Thus, the variant is most likely pathogenic based on the available computational evidence. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -10.017 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.10 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.12 | Likely Benign | 0.40 | Likely Benign | 0.510 | Likely Pathogenic | -4.48 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.08 | Pathogenic | 0.14 | Tolerated | 0.2024 | 0.2240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1668C>G | N556K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N556K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions from FoldX, Rosetta, premPS, and SIFT; pathogenic predictions from SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support this dichotomy: AlphaMissense‑Optimized predicts pathogenicity, the SGM‑Consensus (a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts a benign effect. Based on the preponderance of evidence, the variant is most likely pathogenic, and this conclusion is consistent with the absence of ClinVar annotation (i.e., no conflicting benign classification). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015078 | Structured | 0.008655 | Uncertain | 0.925 | 0.225 | 0.000 | -10.017 | Likely Pathogenic | 0.968 | Likely Pathogenic | Likely Pathogenic | 0.10 | Likely Benign | 0.1 | 0.14 | Likely Benign | 0.12 | Likely Benign | 0.40 | Likely Benign | 0.510 | Likely Pathogenic | -4.48 | Deleterious | 0.999 | Probably Damaging | 0.997 | Probably Damaging | -1.08 | Pathogenic | 0.14 | Tolerated | 0.2024 | 0.2240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1896C>A | N632K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632K is not reported in ClinVar and is present in gnomAD. Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the majority of other in silico predictors (SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized) classify it as pathogenic; premPS is uncertain. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) predicts benign. Overall, the preponderance of evidence points to a pathogenic effect for N632K, and this assessment does not contradict the ClinVar status, which currently has no entry for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | 6-33440948-C-A | -13.266 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.12 | Likely Benign | 0.03 | Likely Benign | 0.95 | Ambiguous | 0.766 | Likely Pathogenic | -5.14 | Deleterious | 0.983 | Probably Damaging | 0.714 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.2375 | 0.4897 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.1896C>G | N632K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N632K is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that indicate a benign effect include FoldX, Rosetta, and Foldetta, whereas the majority of other in‑silico predictors (REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus) predict a pathogenic outcome; premPS is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Based on the overall consensus of the majority of tools, the variant is most likely pathogenic, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.042364 | Structured | 0.041437 | Uncertain | 0.938 | 0.254 | 0.000 | -13.266 | Likely Pathogenic | 0.974 | Likely Pathogenic | Likely Pathogenic | -0.06 | Likely Benign | 0.2 | 0.12 | Likely Benign | 0.03 | Likely Benign | 0.95 | Ambiguous | 0.766 | Likely Pathogenic | -5.14 | Deleterious | 0.983 | Probably Damaging | 0.714 | Possibly Damaging | -1.43 | Pathogenic | 0.01 | Affected | 3.37 | 34 | 0.2375 | 0.4897 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||
| c.1905C>A | N635K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N635K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict pathogenicity: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also indicates a likely pathogenic outcome. Predictions from FoldX, Rosetta, Foldetta, and premPS are uncertain and are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM Consensus as likely pathogenic, and Foldetta as uncertain. Overall, the preponderance of evidence points to a pathogenic effect for N635K, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -13.144 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.60 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.68 | Ambiguous | 0.85 | Ambiguous | 0.332 | Likely Benign | -5.64 | Deleterious | 0.949 | Possibly Damaging | 0.550 | Possibly Damaging | 2.92 | Benign | 0.00 | Affected | 0.2125 | 0.2510 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1905C>G | N635K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N635K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL and FATHMM, whereas a majority of tools predict a pathogenic impact: PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also classifies the variant as Likely Pathogenic. High‑accuracy assessments show AlphaMissense‑Optimized as Pathogenic and the SGM Consensus as Likely Pathogenic, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. Overall, the preponderance of evidence from multiple in silico predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict any existing ClinVar annotation (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.039760 | Structured | 0.060246 | Uncertain | 0.900 | 0.252 | 0.000 | -13.144 | Likely Pathogenic | 0.967 | Likely Pathogenic | Likely Pathogenic | 0.60 | Ambiguous | 0.1 | 0.75 | Ambiguous | 0.68 | Ambiguous | 0.85 | Ambiguous | 0.332 | Likely Benign | -5.64 | Deleterious | 0.949 | Possibly Damaging | 0.550 | Possibly Damaging | 2.92 | Benign | 0.00 | Affected | 0.2125 | 0.2510 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.1950T>A | N650K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N650K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Foldetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and premPS. High‑accuracy assessments give a pathogenic verdict from AlphaMissense‑Optimized and the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), while Foldetta predicts a benign effect on protein stability. Overall, the majority of evidence points to a pathogenic impact, and this conclusion is not contradicted by ClinVar, which contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | -13.078 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.17 | Likely Benign | 0.92 | Ambiguous | 0.269 | Likely Benign | -5.98 | Deleterious | 0.995 | Probably Damaging | 0.807 | Possibly Damaging | 3.02 | Benign | 0.03 | Affected | 3.37 | 30 | 0.3028 | 0.3360 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||
| c.1950T>G | N650K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N650K is not reported in ClinVar and is present in gnomAD (ID 6‑33441209‑T‑G). Prediction tools that indicate a benign effect include REVEL, FoldX, FATHMM, and Foldetta, whereas a majority of tools predict pathogenicity: SGM‑Consensus, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Two tools (premPS and Rosetta) give uncertain results. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign. Overall, the majority of predictions lean toward pathogenicity, indicating the variant is most likely pathogenic, and this is consistent with the lack of a ClinVar entry; there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.086953 | Structured | 0.361944 | Uncertain | 0.961 | 0.357 | 0.000 | 6-33441209-T-G | -13.078 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | -0.33 | Likely Benign | 0.1 | 0.66 | Ambiguous | 0.17 | Likely Benign | 0.92 | Ambiguous | 0.269 | Likely Benign | -5.98 | Deleterious | 0.995 | Probably Damaging | 0.807 | Possibly Damaging | 3.02 | Benign | 0.03 | Affected | 3.37 | 30 | 0.3028 | 0.3360 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||
| c.2007T>A | N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign predictions come from REVEL, FoldX, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus confirms a Likely Pathogenic status, and Foldetta, which integrates FoldX‑MD and Rosetta outputs, yields an uncertain result. Overall, the majority of evidence points toward a pathogenic impact, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.797 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.3 | 1.50 | Ambiguous | 0.95 | Ambiguous | 0.94 | Ambiguous | 0.243 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.2647 | 0.3312 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2007T>G | N669K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N669K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts pathogenicity, SGM‑Consensus concurs, and the Foldetta stability analysis is inconclusive and therefore not used as evidence. No other tools provide definitive support for benignity. Consequently, the preponderance of evidence points to a pathogenic impact. This conclusion is not contradicted by ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.142424 | Structured | 0.086615 | Uncertain | 0.872 | 0.380 | 0.000 | -10.797 | Likely Pathogenic | 0.957 | Likely Pathogenic | Likely Pathogenic | 0.39 | Likely Benign | 0.3 | 1.50 | Ambiguous | 0.95 | Ambiguous | 0.94 | Ambiguous | 0.243 | Likely Benign | -5.35 | Deleterious | 0.999 | Probably Damaging | 0.989 | Probably Damaging | 3.41 | Benign | 0.03 | Affected | 0.2647 | 0.3312 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2025C>A | N675K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N675K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, Rosetta, and FATHMM, whereas pathogenic calls are made by FoldX, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. Uncertain results are reported for Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments give a mixed picture: AlphaMissense‑Optimized is inconclusive, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta remains uncertain. Overall, the majority of evidence points toward a pathogenic effect, and this conclusion does not conflict with ClinVar, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -12.851 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 2.88 | Destabilizing | 1.2 | 0.06 | Likely Benign | 1.47 | Ambiguous | 0.74 | Ambiguous | 0.177 | Likely Benign | -4.75 | Deleterious | 0.993 | Probably Damaging | 0.688 | Possibly Damaging | 3.44 | Benign | 0.02 | Affected | 0.2424 | 0.6040 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2025C>G | N675K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N675K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, Rosetta, and FATHMM, whereas a majority (FoldX, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default) predict a pathogenic impact. Tools with inconclusive results are Foldetta, premPS, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the balance of evidence favors a pathogenic classification for N675K, and this conclusion does not contradict any ClinVar annotation, as none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.129801 | Structured | 0.111024 | Uncertain | 0.513 | 0.333 | 0.000 | -12.851 | Likely Pathogenic | 0.898 | Likely Pathogenic | Ambiguous | 2.88 | Destabilizing | 1.2 | 0.06 | Likely Benign | 1.47 | Ambiguous | 0.74 | Ambiguous | 0.177 | Likely Benign | -4.75 | Deleterious | 0.993 | Probably Damaging | 0.688 | Possibly Damaging | 3.44 | Benign | 0.02 | Affected | 0.2424 | 0.6040 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.2157C>A | N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. 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. The remaining tools (FoldX, Rosetta, ESM1b, and Foldetta) give uncertain or inconclusive results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as benign, and Foldetta as uncertain. Overall, the majority of reliable predictions indicate a benign impact, and this conclusion does not contradict the lack of ClinVar annotation. Thus, the variant is most likely benign. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.250 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2157C>G | N719K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N719K is not reported in ClinVar and is absent from gnomAD. Consensus from multiple in silico predictors shows a predominance of benign calls: REVEL, premPS, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized all predict a neutral effect, whereas polyPhen‑2 (HumDiv and HumVar) and AlphaMissense‑Default predict pathogenicity. FoldX, Rosetta, ESM1b, and Foldetta are inconclusive. High‑accuracy assessment further supports a benign interpretation: AlphaMissense‑Optimized is benign; the SGM Consensus—derived from the majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN—also yields a benign outcome; Foldetta remains uncertain. 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. | GAP | 0.384043 | Structured | 0.445381 | Uncertain | 0.961 | 0.386 | 0.000 | -7.454 | In-Between | 0.651 | Likely Pathogenic | Likely Benign | -0.64 | Ambiguous | 0.0 | -0.62 | Ambiguous | -0.63 | Ambiguous | 0.42 | Likely Benign | 0.244 | Likely Benign | -1.84 | Neutral | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 2.80 | Benign | 0.55 | Tolerated | 0.1424 | 0.3112 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2181C>A | N727K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N727K is catalogued in gnomAD (ID 6‑33441646‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions come from REVEL, FoldX, Rosetta, SIFT, and the protein‑folding stability method Foldetta; pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Default, and the consensus score SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, SGM Consensus indicates likely pathogenic, and Foldetta reports benign stability. Overall, the majority of evidence points to a pathogenic effect, 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 | 0.538167 | Disordered | 0.442107 | Uncertain | 0.843 | 0.542 | 0.625 | 6-33441646-C-A | 1 | 6.19e-7 | -10.601 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | -0.12 | Likely Benign | 0.2 | -0.44 | Likely Benign | -0.28 | Likely Benign | 0.86 | Ambiguous | 0.148 | Likely Benign | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.18 | Pathogenic | 0.12 | Tolerated | 3.59 | 7 | 0.2002 | 0.5590 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||
| c.2181C>G | N727K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N727K 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 predict 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. This conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.538167 | Disordered | 0.442107 | Uncertain | 0.843 | 0.542 | 0.625 | -10.601 | Likely Pathogenic | 0.884 | Likely Pathogenic | Ambiguous | -0.12 | Likely Benign | 0.2 | -0.44 | Likely Benign | -0.28 | Likely Benign | 0.86 | Ambiguous | 0.148 | Likely Benign | -3.82 | Deleterious | 0.998 | Probably Damaging | 0.994 | Probably Damaging | 2.18 | Pathogenic | 0.12 | Tolerated | 3.59 | 7 | 0.2002 | 0.5590 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||
| c.2187C>A | N729K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729K has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. Tools with uncertain or mixed results are Foldetta (protein‑folding stability) and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized reports a benign effect; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign; Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict the current ClinVar status, which contains no report for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.101 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | -0.03 | Likely Benign | 0.1 | 1.92 | Ambiguous | 0.95 | Ambiguous | 0.12 | Likely Benign | 0.036 | Likely Benign | -1.39 | Neutral | 0.109 | Benign | 0.033 | Benign | 3.51 | Benign | 0.47 | Tolerated | 0.1948 | 0.3612 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2187C>G | N729K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N729K has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus call (Likely Benign). Only AlphaMissense‑Default predicts a pathogenic outcome. Tools with uncertain or mixed results are Foldetta (protein‑folding stability) and Rosetta. High‑accuracy assessments: AlphaMissense‑Optimized reports a benign effect; the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also indicates likely benign; Foldetta’s stability prediction is inconclusive. Overall, the majority of evidence points to a benign impact for the variant, and this conclusion does not contradict the current ClinVar status, which contains no report for this change. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.750527 | Disordered | 0.426547 | Uncertain | 0.651 | 0.583 | 0.625 | -5.101 | Likely Benign | 0.648 | Likely Pathogenic | Likely Benign | -0.03 | Likely Benign | 0.1 | 1.92 | Ambiguous | 0.95 | Ambiguous | 0.12 | Likely Benign | 0.036 | Likely Benign | -1.39 | Neutral | 0.109 | Benign | 0.033 | Benign | 3.51 | Benign | 0.47 | Tolerated | 0.1948 | 0.3612 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||
| c.2292C>A | N764K 2D AIThe SynGAP1 missense variant N764K is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates 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 classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.867 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.073 | Likely Benign | -1.36 | Neutral | 0.992 | Probably Damaging | 0.921 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.2005 | 0.3539 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2292C>G | N764K 2D AIThe SynGAP1 missense variant N764K is not reported in ClinVar and has no entries in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates 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 classification, and this assessment does not contradict any ClinVar status because no ClinVar entry exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.380708 | Structured | 0.919527 | Binding | 0.305 | 0.861 | 0.250 | -5.867 | Likely Benign | 0.892 | Likely Pathogenic | Ambiguous | 0.073 | Likely Benign | -1.36 | Neutral | 0.992 | Probably Damaging | 0.921 | Probably Damaging | 2.66 | Benign | 0.02 | Affected | 0.2005 | 0.3539 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2334C>A | N778K 2D AIThe SynGAP1 missense variant N778K is catalogued in gnomAD (ID 6‑33442492‑C‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, ESM1b, and FATHMM; pathogenic predictions 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, reflecting the majority of benign calls. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain, and Foldetta data are not available. Overall, the majority of evidence points toward a benign effect, and this is consistent with the lack of a ClinVar pathogenic classification. Therefore, the variant is most likely benign, with no contradiction to ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | 6-33442492-C-A | -6.768 | Likely Benign | 0.798 | Likely Pathogenic | Ambiguous | 0.113 | Likely Benign | -1.57 | Neutral | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 4.27 | Benign | 0.18 | Tolerated | 3.64 | 6 | 0.2037 | 0.5883 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||
| c.2334C>G | N778K 2D AIThe SynGAP1 missense variant N778K has no ClinVar record and is not listed in gnomAD. 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. The high‑accuracy consensus, SGM‑Consensus, is derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, yielding a “Likely Benign” classification. AlphaMissense‑Optimized returns an uncertain result, and Foldetta (a protein‑folding stability method combining FoldX‑MD and Rosetta) has no available output for this variant. Overall, the preponderance of evidence points to a benign effect. 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 Benign | 0.494003 | Structured | 0.853922 | Binding | 0.288 | 0.887 | 0.500 | -6.768 | Likely Benign | 0.798 | Likely Pathogenic | Ambiguous | 0.114 | Likely Benign | -1.57 | Neutral | 0.925 | Possibly Damaging | 0.932 | Probably Damaging | 4.27 | Benign | 0.18 | Tolerated | 3.64 | 6 | 0.2037 | 0.5883 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.237C>A | N79K 2D AIThe SynGAP1 missense variant N79K is listed in gnomAD (ID 6‑33425845‑C‑A) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments further support a benign classification: AlphaMissense‑Optimized scores benign and the SGM‑Consensus indicates “Likely Benign.” No Foldetta stability prediction is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for the variant, and this conclusion is not contradicted by any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.618285 | Disordered | 0.457064 | Uncertain | 0.290 | 0.876 | 0.375 | 6-33425845-C-A | 1 | 6.20e-7 | -2.811 | Likely Benign | 0.422 | Ambiguous | Likely Benign | 0.030 | Likely Benign | -0.91 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.22 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1883 | 0.3929 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||
| c.237C>G | N79K 2D AIThe SynGAP1 missense variant N79K is listed in gnomAD (ID 6‑33425845‑C‑G) but has no ClinVar entry. Functional prediction tools that agree on a benign effect include REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN). Only SIFT predicts a pathogenic outcome, while AlphaMissense‑Default remains uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as likely benign; Foldetta stability analysis is unavailable. Overall, the majority of evidence points to a benign impact. There is no ClinVar classification to contradict this conclusion. 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 | 0.618285 | Disordered | 0.457064 | Uncertain | 0.290 | 0.876 | 0.375 | 6-33425845-C-G | 1 | 6.20e-7 | -2.811 | Likely Benign | 0.422 | Ambiguous | Likely Benign | 0.030 | Likely Benign | -0.91 | Neutral | 0.001 | Benign | 0.000 | Benign | 4.22 | Benign | 0.00 | Affected | 4.32 | 1 | 0.1883 | 0.3929 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||
| c.2514C>A | N838K 2D AIThe SynGAP1 missense variant N838K is listed in ClinVar with an “Uncertain” status (ClinVar ID 1377909.0) and is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, SIFT, and FATHMM, whereas those that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, 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 “Uncertain,” SGM‑Consensus as “Likely Pathogenic,” 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 leans toward a pathogenic interpretation, which does not contradict the current ClinVar “Uncertain” classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | Uncertain | 2 | -8.470 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.097 | Likely Benign | -2.78 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.69 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.2187 | 0.3866 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||
| c.2514C>G | N838K 2D AIThe SynGAP1 missense variant N838K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL, SIFT, and FATHMM, whereas pathogenic calls arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, ESM1b, and AlphaMissense‑Default. The high‑accuracy consensus, SGM‑Consensus, classifies the variant as Likely Pathogenic, while AlphaMissense‑Optimized yields an Uncertain result and Foldetta data are unavailable. Overall, the majority of evidence points toward a pathogenic effect, and this assessment does not conflict with ClinVar, which currently contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.622677 | Disordered | 0.613320 | Binding | 0.276 | 0.861 | 0.250 | -8.470 | Likely Pathogenic | 0.862 | Likely Pathogenic | Ambiguous | 0.097 | Likely Benign | -2.78 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 2.69 | Benign | 0.16 | Tolerated | 3.77 | 5 | 0.2187 | 0.3866 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.2568C>A | N856K 2D AIThe SynGAP1 missense variant N856K 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 majority of high‑accuracy predictors (AlphaMissense‑Optimized and the SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, but these are the only tools in disagreement. The AlphaMissense‑Default score is uncertain, and no Foldetta stability assessment is available. Overall, the preponderance of evidence points to a benign effect for N856K, and this conclusion is not in conflict with any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.637480 | Disordered | 0.477615 | Uncertain | 0.263 | 0.827 | 0.500 | -3.511 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.51 | Neutral | 0.965 | Probably Damaging | 0.721 | Possibly Damaging | 4.19 | Benign | 0.26 | Tolerated | 0.2065 | 0.6252 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2568C>G | N856K 2D AIThe SynGAP1 missense variant N856K 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 majority of high‑accuracy predictors—AlphaMissense‑Optimized and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—also support a benign classification. In contrast, polyPhen‑2 (HumDiv and HumVar) predict a pathogenic impact, but these are the only tools in disagreement. No Foldetta stability analysis is available, so it does not influence the assessment. Overall, the preponderance of evidence points to a benign effect for N856K, 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 | 0.637480 | Disordered | 0.477615 | Uncertain | 0.263 | 0.827 | 0.500 | -3.511 | Likely Benign | 0.429 | Ambiguous | Likely Benign | 0.079 | Likely Benign | -1.51 | Neutral | 0.965 | Probably Damaging | 0.721 | Possibly Damaging | 4.19 | Benign | 0.26 | Tolerated | 0.2065 | 0.6252 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2586C>A | N862K 2D AIThe SynGAP1 missense variant N862K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. ESM1b is uncertain. 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, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.564559 | Binding | 0.257 | 0.791 | 0.250 | -7.000 | In-Between | 0.766 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -1.87 | Neutral | 0.995 | Probably Damaging | 0.946 | Probably Damaging | 4.10 | Benign | 0.20 | Tolerated | 0.2313 | 0.5469 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2586C>G | N862K 2D AIThe SynGAP1 missense variant N862K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, SIFT, FATHMM, and AlphaMissense‑Optimized; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and AlphaMissense‑Default. ESM1b is uncertain. 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, and Foldetta results are unavailable. Overall, the majority of evidence points to a benign effect. This conclusion is consistent with the lack of ClinVar annotation and does not contradict any existing clinical classification. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.525368 | Disordered | 0.564559 | Binding | 0.257 | 0.791 | 0.250 | -7.000 | In-Between | 0.766 | Likely Pathogenic | Likely Benign | 0.084 | Likely Benign | -1.87 | Neutral | 0.995 | Probably Damaging | 0.946 | Probably Damaging | 4.10 | Benign | 0.20 | Tolerated | 0.2313 | 0.5469 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.2787C>A | N929K 2D AIThe SynGAP1 missense variant N929K is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign—REVEL—and pathogenic—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status; Foldetta results are not available. Taken together, the preponderance of evidence supports a pathogenic interpretation for N929K, and this conclusion is consistent with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.986867 | Binding | 0.321 | 0.851 | 0.375 | -10.041 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.182 | Likely Benign | -4.35 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.48 | Pathogenic | 0.00 | Affected | 0.2098 | 0.6046 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.2787C>G | N929K 2D AIThe SynGAP1 missense variant N929K is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into two groups: benign—REVEL—and pathogenic—PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, also reports a likely pathogenic outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized predicts pathogenicity, and the SGM‑Consensus confirms a likely pathogenic status; Foldetta results are not available. Taken together, the preponderance of evidence supports a pathogenic interpretation for N929K, and this conclusion is consistent with the absence of a ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.986867 | Binding | 0.321 | 0.851 | 0.375 | -10.041 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 0.182 | Likely Benign | -4.35 | Deleterious | 0.999 | Probably Damaging | 0.996 | Probably Damaging | 1.48 | Pathogenic | 0.00 | Affected | 0.2098 | 0.6046 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3081C>A | N1027K 2D AIThe SynGAP1 missense variant N1027K 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, while those 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, classifies the variant as Likely Benign. High‑accuracy assessments show AlphaMissense‑Optimized as Uncertain, and the SGM‑Consensus result is benign; Foldetta predictions are unavailable. Overall, the balance of evidence favors a benign interpretation, and this conclusion does not contradict any ClinVar annotation (none exists). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 0.1808 | 0.6079 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3081C>G | N1027K 2D AIThe SynGAP1 missense variant N1027K 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 high‑accuracy consensus from SGM (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Benign, and AlphaMissense‑Optimized is 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 consistent with the lack of ClinVar annotation, so there is no contradiction with ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.831250 | Disordered | 0.994357 | Binding | 0.347 | 0.745 | 0.500 | -3.177 | Likely Benign | 0.841 | Likely Pathogenic | Ambiguous | 0.063 | Likely Benign | -0.64 | Neutral | 0.481 | Possibly Damaging | 0.220 | Benign | 2.81 | Benign | 0.65 | Tolerated | 0.1808 | 0.6079 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3270T>A | N1090K 2D AIThe SynGAP1 missense variant N1090K is reported in ClinVar as “None” and is present in gnomAD (ID 6‑33443822‑T‑A). Functional 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; a Foldetta stability analysis is unavailable. Overall, the majority of predictions (six benign vs. four pathogenic) and the consensus result lean toward a benign interpretation. This conclusion does not contradict ClinVar, which currently has no pathogenic classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | 6-33443822-T-A | 2 | 1.28e-6 | -3.423 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.053 | Likely Benign | -1.52 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.73 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.2147 | 0.6121 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||
| c.3270T>G | N1090K 2D AIThe SynGAP1 missense variant N1090K has no ClinVar entry and is not reported in gnomAD. Prediction tools that indicate 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. The overall balance of evidence leans toward a benign interpretation, and this is consistent with the lack of a ClinVar classification. Thus, the variant is most likely benign and does not contradict ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.896620 | Disordered | 0.979886 | Binding | 0.341 | 0.887 | 1.000 | -3.423 | Likely Benign | 0.963 | Likely Pathogenic | Likely Pathogenic | 0.053 | Likely Benign | -1.52 | Neutral | 0.997 | Probably Damaging | 0.992 | Probably Damaging | 2.73 | Benign | 0.18 | Tolerated | 3.77 | 5 | 0.2147 | 0.6121 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.3435C>A | N1145K 2D AIThe SynGAP1 missense variant N1145K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, and FATHMM, while those that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as “Uncertain” and the SGM‑Consensus as “Likely Benign”; Foldetta results are unavailable. Overall, the balance of evidence leans toward a benign interpretation, and this conclusion does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.545 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.50 | Benign | 0.03 | Affected | 0.1959 | 0.6018 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3435C>G | N1145K 2D AIThe SynGAP1 missense variant N1145K is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN), which collectively suggest a likely benign impact. Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The high‑accuracy AlphaMissense‑Optimized result is uncertain, and Foldetta stability analysis is unavailable. Overall, the balance of evidence leans toward a benign interpretation, with no conflict with ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.922952 | Disordered | 0.722723 | Binding | 0.284 | 0.850 | 1.000 | -2.545 | Likely Benign | 0.814 | Likely Pathogenic | Ambiguous | 0.440 | Likely Benign | -2.40 | Neutral | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 5.50 | Benign | 0.03 | Affected | 0.1959 | 0.6018 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3480C>A | N1160K 2D AIThe SynGAP1 missense variant N1160K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, 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 (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability analysis is available for this residue. 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 | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.768 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.188 | Likely Benign | -3.92 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.83 | Pathogenic | 0.04 | Affected | 0.1919 | 0.5017 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3480C>G | N1160K 2D AIThe SynGAP1 missense variant N1160K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools show a split: benign calls come from REVEL and ESM1b, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, 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 (derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also indicates Likely Pathogenic. No Foldetta stability analysis is available for this residue. 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 | 0.585406 | Disordered | 0.861611 | Binding | 0.361 | 0.836 | 0.375 | -3.768 | Likely Benign | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.189 | Likely Benign | -3.92 | Deleterious | 0.997 | Probably Damaging | 0.995 | Probably Damaging | 1.83 | Pathogenic | 0.04 | Affected | 0.1919 | 0.5017 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3639C>A | N1213K 2D AIThe SynGAP1 missense variant N1213K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are limited: AlphaMissense‑Optimized yields an uncertain result, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta data are unavailable. Overall, the majority of evidence (five pathogenic vs. three benign) points toward a pathogenic effect. This conclusion is not contradicted by ClinVar status, which contains no entry for this variant. Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | -11.303 | Likely Pathogenic | 0.885 | Likely Pathogenic | Ambiguous | 0.059 | Likely Benign | -1.58 | Neutral | 0.920 | Possibly Damaging | 0.652 | Possibly Damaging | 2.75 | Benign | 0.05 | Affected | 0.1506 | 0.3250 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3639C>G | N1213K 2D AIThe SynGAP1 missense variant N1213K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, PROVEAN, and FATHMM, while pathogenic predictions arise from polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are limited: AlphaMissense‑Optimized yields an uncertain result, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive due to a 2‑vs‑2 split, and Foldetta data are unavailable. Overall, the majority of evidence (five pathogenic vs. three benign) points toward a pathogenic effect. This conclusion is not contradicted by ClinVar status, which contains no entry for this variant. Thus, based on current predictions, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Coiled-coil | 0.580690 | Disordered | 0.521638 | Binding | 0.888 | 0.561 | 0.500 | -11.303 | Likely Pathogenic | 0.885 | Likely Pathogenic | Ambiguous | 0.058 | Likely Benign | -1.58 | Neutral | 0.920 | Possibly Damaging | 0.652 | Possibly Damaging | 2.75 | Benign | 0.05 | Affected | 0.1506 | 0.3250 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||||
| c.3918C>A | N1306K 2D AIThe SynGAP1 missense variant N1306K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -3.021 | Likely Benign | 0.585 | Likely Pathogenic | Likely Benign | 0.140 | Likely Benign | -4.00 | Deleterious | 0.532 | Possibly Damaging | 0.327 | Benign | 2.61 | Benign | 0.00 | Affected | 0.2375 | 0.6234 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3918C>G | N1306K 2D AIThe SynGAP1 missense variant N1306K is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 HumVar, ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, polyPhen‑2 HumDiv, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized classifying the variant as benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is inconclusive due to a 2‑to‑2 split, and Foldetta results are unavailable. Overall, the majority of evidence points toward a benign impact. This conclusion does not contradict ClinVar status, as the variant has no ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.795062 | Disordered | 0.902190 | Binding | 0.367 | 0.888 | 0.875 | -3.021 | Likely Benign | 0.585 | Likely Pathogenic | Likely Benign | 0.177 | Likely Benign | -4.00 | Deleterious | 0.532 | Possibly Damaging | 0.327 | Benign | 2.61 | Benign | 0.00 | Affected | 0.2375 | 0.6234 | 1 | 0 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||||
| c.3948T>A | N1316K 2D AIThe SynGAP1 missense variant N1316K is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451822‑T‑A). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, 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 benign vs 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict any ClinVar annotation (none). 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. | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451822-T-A | -3.815 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.044 | Likely Benign | -3.27 | Deleterious | 0.414 | Benign | 0.063 | Benign | 4.00 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2065 | 0.5500 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.3948T>G | N1316K 2D AIThe SynGAP1 missense variant N1316K is not reported in ClinVar (ClinVar status: none) but is present in gnomAD (ID 6‑33451822‑T‑G). Prediction tools that agree on a benign effect include REVEL, polyPhen‑2 (HumDiv and HumVar), ESM1b, FATHMM, and AlphaMissense‑Optimized. Tools that predict a pathogenic effect are PROVEAN, SIFT, 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 benign + 2 pathogenic), and Foldetta results are unavailable. Overall, the majority of evidence points to a benign impact, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.899122 | Disordered | 0.971970 | Binding | 0.380 | 0.885 | 0.750 | 6-33451822-T-G | -3.815 | Likely Benign | 0.699 | Likely Pathogenic | Likely Benign | 0.044 | Likely Benign | -3.27 | Deleterious | 0.414 | Benign | 0.063 | Benign | 4.00 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2065 | 0.5500 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.4002C>A | N1334K 2D AIThe SynGAP1 missense variant N1334K is listed in gnomAD (ID 6‑33451876‑C‑A) but has no ClinVar record. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. The high‑accuracy consensus (SGM Consensus) derived 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 (three), and the high‑accuracy methods do not overturn this trend. 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. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | 6-33451876-C-A | -4.875 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.109 | Likely Benign | -3.49 | Deleterious | 0.979 | Probably Damaging | 0.756 | Possibly Damaging | 3.54 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2355 | 0.5163 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.4002C>G | N1334K 2D AIThe SynGAP1 missense variant N1334K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, whereas pathogenic predictions arise from PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are limited: AlphaMissense‑Optimized remains inconclusive; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is a 2‑to‑2 tie and therefore unavailable; Foldetta predictions are not provided. Overall, the balance of evidence favors a pathogenic effect for N1334K. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical databases. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.915074 | Disordered | 0.960403 | Binding | 0.406 | 0.734 | 0.875 | -4.875 | Likely Benign | 0.934 | Likely Pathogenic | Ambiguous | 0.120 | Likely Benign | -3.49 | Deleterious | 0.979 | Probably Damaging | 0.756 | Possibly Damaging | 3.54 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2355 | 0.5163 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||
| c.4017C>A | N1339K 2D AIThe SynGAP1 missense variant N1339K is listed in gnomAD (ID 6‑33451891‑C‑A) but has no ClinVar record. Functional prediction tools cluster into two groups: benign predictions come from REVEL, ESM1b, and FATHMM, while pathogenic predictions arise from PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and AlphaMissense‑Default. AlphaMissense‑Optimized returns an uncertain result. The high‑accuracy consensus (SGM Consensus) – a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN – is inconclusive (two pathogenic, two benign). Foldetta, a protein‑folding stability method, has no reported output for this variant. Overall, the majority of available tools (five pathogenic vs. three benign) predict a deleterious effect. The variant is most likely pathogenic based on current predictions, and this assessment does not contradict any ClinVar status, as none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | 6-33451891-C-A | -3.009 | Likely Benign | 0.872 | Likely Pathogenic | Ambiguous | 0.169 | Likely Benign | -3.56 | Deleterious | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2201 | 0.6507 | 0 | 1 | -0.4 | 14.07 | |||||||||||||||||||||||||||||||||||||
| c.4017C>G | N1339K 2D AISynGAP1 missense variant N1339K is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include REVEL, ESM1b, and FATHMM, whereas a majority of tools (PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default) predict a pathogenic impact; AlphaMissense‑Optimized is uncertain. High‑accuracy assessments are inconclusive: AlphaMissense‑Optimized remains uncertain, the SGM Consensus (a majority vote among AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is a 2‑to‑2 tie, and Foldetta results are unavailable. Overall, the balance of evidence favors a pathogenic 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. | 0.771762 | Disordered | 0.977585 | Binding | 0.396 | 0.687 | 1.000 | -3.009 | Likely Benign | 0.872 | Likely Pathogenic | Ambiguous | 0.181 | Likely Benign | -3.56 | Deleterious | 0.980 | Probably Damaging | 0.968 | Probably Damaging | 2.90 | Benign | 0.00 | Affected | 3.77 | 5 | 0.2201 | 0.6507 | 0 | 1 | -0.4 | 14.07 | ||||||||||||||||||||||||||||||||||||||
| 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.735T>A | N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split assessment: benign predictions come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic predictions are reported by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The high‑accuracy consensus, SGM, aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN and yields a majority pathogenic verdict. Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, classifies the variant as benign. Overall, the majority of individual predictors and the SGM consensus favor a pathogenic effect, while Foldetta and a subset of benign tools suggest stability preservation. Given the predominance of pathogenic predictions and the absence of ClinVar annotation, the variant is most likely pathogenic and does not contradict any existing ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.110 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.32 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.16 | Likely Benign | 0.83 | Ambiguous | 0.474 | Likely Benign | -4.86 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.88 | Benign | 0.01 | Affected | 0.2271 | 0.5645 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.735T>G | N245K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N245K is not reported in ClinVar and has no entries in gnomAD. Functional prediction tools show a split: benign calls come from REVEL, FoldX, Rosetta, and FATHMM, whereas pathogenic calls are made by PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. The SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels the variant as Likely Pathogenic. High‑accuracy assessments further support a deleterious effect: AlphaMissense‑Optimized predicts Pathogenic, the SGM Consensus also indicates Likely Pathogenic, while Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, reports a Benign effect. Overall, the preponderance of evidence—including the high‑accuracy tools—points to a pathogenic impact for N245K, and this conclusion is not contradicted by any ClinVar annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.454136 | Structured | 0.315864 | Uncertain | 0.831 | 0.351 | 0.000 | -12.110 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | -0.32 | Likely Benign | 0.1 | 0.01 | Likely Benign | -0.16 | Likely Benign | 0.83 | Ambiguous | 0.474 | Likely Benign | -4.86 | Deleterious | 0.948 | Possibly Damaging | 0.588 | Possibly Damaging | 5.88 | Benign | 0.01 | Affected | 0.2271 | 0.5645 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.759C>A | N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K resides in the PH domain. ClinVar has no entry for this variant, and it is not reported in gnomAD. Functional prediction tools that classify the variant as benign include FoldX, Foldetta, premPS, and FATHMM. In contrast, the majority of predictors—REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN)—label it pathogenic or likely pathogenic. The high‑accuracy methods give a mixed picture: AlphaMissense‑Optimized predicts pathogenic, the SGM‑Consensus also indicates likely pathogenic, whereas Foldetta, which integrates FoldX‑MD and Rosetta stability outputs, predicts benign. Overall, the preponderance of evidence from standard and high‑accuracy predictors points to a pathogenic effect. This assessment is not contradicted by ClinVar, which currently contains no classification for the variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -15.834 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.0 | 0.90 | Ambiguous | 0.48 | Likely Benign | 0.17 | Likely Benign | 0.663 | Likely Pathogenic | -5.21 | Deleterious | 0.993 | Probably Damaging | 0.979 | Probably Damaging | 5.53 | Benign | 0.03 | Affected | 0.2640 | 0.6592 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.759C>G | N253K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N253K is not reported in ClinVar and is absent from gnomAD. Functional prediction tools fall into two groups: benign predictions come from FoldX, FATHMM, premPS, and Foldetta, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized; Rosetta is uncertain. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as Likely Pathogenic, and Foldetta as Benign. Overall, the majority of tools predict pathogenicity, and the two most reliable predictors also lean pathogenic, whereas only one high‑accuracy tool suggests benign. Therefore, the variant is most likely pathogenic based on current predictions, and this assessment does not contradict the ClinVar status, which has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | PH | 0.513880 | Disordered | 0.201744 | Uncertain | 0.771 | 0.298 | 0.250 | -15.834 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 0.05 | Likely Benign | 0.0 | 0.90 | Ambiguous | 0.48 | Likely Benign | 0.17 | Likely Benign | 0.663 | Likely Pathogenic | -5.21 | Deleterious | 0.993 | Probably Damaging | 0.979 | Probably Damaging | 5.53 | Benign | 0.03 | Affected | 0.2640 | 0.6592 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.768C>A | N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools favor a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this assessment does not contradict ClinVar status, which currently has no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -13.814 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | -0.10 | Likely Benign | 0.06 | Likely Benign | 0.55 | Ambiguous | 0.569 | Likely Pathogenic | -5.02 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.90 | Benign | 0.01 | Affected | 0.1702 | 0.5240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.768C>G | N256K 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant N256K is not reported in ClinVar and is absent from gnomAD. Prediction tools that classify the variant as benign include FoldX, Rosetta, Foldetta, and FATHMM. Those that predict pathogenicity comprise SGM‑Consensus, REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as benign. Overall, the majority of tools support a pathogenic effect, whereas a minority suggest benign. Thus, the variant is most likely pathogenic, and this conclusion is not contradicted by ClinVar status, which currently contains no entry for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.414856 | Structured | 0.234105 | Uncertain | 0.826 | 0.271 | 0.250 | -13.814 | Likely Pathogenic | 1.000 | Likely Pathogenic | Likely Pathogenic | 0.22 | Likely Benign | 0.3 | -0.10 | Likely Benign | 0.06 | Likely Benign | 0.55 | Ambiguous | 0.569 | Likely Pathogenic | -5.02 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.90 | Benign | 0.01 | Affected | 0.1702 | 0.5240 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.786T>A | N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not present in gnomAD. Prediction tools that indicate a benign effect include FoldX, premPS, and FATHMM. Those that predict a pathogenic effect comprise REVEL, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus score (Likely Pathogenic). Uncertain results are reported by Rosetta and Foldetta. High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, the SGM‑Consensus as Likely Pathogenic, and Foldetta as inconclusive. Overall, the majority of evidence points to a pathogenic impact for N262K. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -12.512 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.74 | Ambiguous | 0.33 | Likely Benign | 0.531 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 0.1799 | 0.3413 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| c.786T>G | N262K 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant N262K has no ClinVar entry and is not reported in gnomAD. Functional prediction tools largely disagree: benign predictions come from FoldX, premPS, and FATHMM, while pathogenic predictions are made by REVEL, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized. Uncertain results are reported by Rosetta and Foldetta. The SGM‑Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is “Likely Pathogenic.” High‑accuracy assessments show AlphaMissense‑Optimized as pathogenic, SGM‑Consensus as likely pathogenic, and Foldetta as inconclusive. Taken together, the majority of evidence points to a pathogenic effect for N262K. This conclusion is consistent with the absence of a ClinVar classification, as there is no existing report to contradict the prediction. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.284882 | Structured | 0.399879 | Uncertain | 0.912 | 0.240 | 0.000 | -12.512 | Likely Pathogenic | 0.962 | Likely Pathogenic | Likely Pathogenic | 0.47 | Likely Benign | 0.2 | 1.00 | Ambiguous | 0.74 | Ambiguous | 0.33 | Likely Benign | 0.532 | Likely Pathogenic | -5.13 | Deleterious | 0.997 | Probably Damaging | 0.986 | Probably Damaging | 5.84 | Benign | 0.02 | Affected | 0.1799 | 0.3413 | 1 | 0 | -0.4 | 14.07 | |||||||||||||||||||||||||||||
| 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.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.1034T>A | L345Q 2D  3DClick to see structure in 3D Viewer AISynGAP1 missense variant L345Q is not reported in ClinVar and is absent from gnomAD. Prediction tools cluster into benign (REVEL, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) and pathogenic (premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, FATHMM). FoldX, Rosetta, and Foldetta give uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive, and Foldetta is unavailable. Overall, the majority of predictions lean toward pathogenicity, while the single high‑accuracy tool that is definitive is benign. Thus, the variant is most likely pathogenic based on the collective evidence, and this assessment does not contradict the absence of a ClinVar entry. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | C2 | 0.260850 | Structured | 0.354989 | Uncertain | 0.936 | 0.478 | 0.125 | -6.034 | Likely Benign | 0.213 | Likely Benign | Likely Benign | 1.32 | Ambiguous | 0.1 | 0.86 | Ambiguous | 1.09 | Ambiguous | 1.26 | Destabilizing | 0.218 | Likely Benign | -3.67 | Deleterious | 0.993 | Probably Damaging | 0.844 | Possibly Damaging | 1.82 | Pathogenic | 0.03 | Affected | 0.0937 | 0.0842 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||
| c.1058T>A | L353Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 L353Q missense variant has no ClinVar entry and is absent from gnomAD. Among in‑silico predictors, only REVEL classifies it as benign, whereas the majority—FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, FATHMM, AlphaMissense‑Default, and the SGM‑Consensus—label it pathogenic. Predictions marked uncertain include Rosetta, Foldetta, ESM1b, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) as likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) as uncertain. Overall, the preponderance of pathogenic predictions outweighs the single benign call, and no ClinVar record contradicts this assessment. Thus, the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.137348 | Structured | 0.373584 | Uncertain | 0.926 | 0.315 | 0.000 | -7.074 | In-Between | 0.884 | Likely Pathogenic | Ambiguous | 2.38 | Destabilizing | 0.2 | 1.41 | Ambiguous | 1.90 | Ambiguous | 2.00 | Destabilizing | 0.388 | Likely Benign | -3.56 | Deleterious | 0.947 | Possibly Damaging | 0.556 | Possibly Damaging | 1.30 | Pathogenic | 0.01 | Affected | 0.1098 | 0.1303 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1100T>A | L367Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L367Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that indicate a benign effect include REVEL, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, AlphaMissense‑Default, AlphaMissense‑Optimized, and ESM1b. Tools that predict a pathogenic effect are SIFT and FATHMM. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports the variant as “Likely Benign.” High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as benign, while Foldetta (combining FoldX‑MD and Rosetta outputs) yields an uncertain result. 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 | 0.370445 | Structured | 0.441805 | Uncertain | 0.790 | 0.657 | 0.250 | -3.432 | Likely Benign | 0.150 | Likely Benign | Likely Benign | 1.09 | Ambiguous | 0.3 | 1.63 | Ambiguous | 1.36 | Ambiguous | 0.31 | Likely Benign | 0.061 | Likely Benign | 0.38 | Neutral | 0.002 | Benign | 0.002 | Benign | 1.65 | Pathogenic | 0.02 | Affected | 0.1615 | 0.0973 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1205T>A | L402Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L402Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to FATHMM, whereas the remaining 13 tools (SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized) uniformly predict a pathogenic impact. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized scores the variant as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it Likely Pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also predicts pathogenicity. No prediction or stability result is missing or inconclusive. Consequently, the variant is most likely pathogenic based on the collective computational evidence, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | C2 | 0.243554 | Structured | 0.431978 | Uncertain | 0.961 | 0.383 | 0.000 | -13.403 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.93 | Destabilizing | 0.0 | 2.55 | Destabilizing | 2.74 | Destabilizing | 2.09 | Destabilizing | 0.523 | Likely Pathogenic | -4.52 | Deleterious | 0.999 | Probably Damaging | 0.957 | Probably Damaging | 3.69 | Benign | 0.00 | Affected | 0.1384 | 0.1173 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1247T>A | L416Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L416Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all predict benign. Only two tools, polyPhen‑2 (HumDiv and HumVar), predict a pathogenic outcome. Stability‑based methods (FoldX, Rosetta, Foldetta, premPS) are inconclusive. High‑accuracy assessments reinforce the benign prediction: AlphaMissense‑Optimized is benign, the SGM‑Consensus is benign, and Foldetta remains uncertain. Overall, the evidence strongly supports a benign classification for this variant, and this conclusion is consistent with the absence of any ClinVar pathogenic annotation. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.104810 | Structured | 0.336105 | Uncertain | 0.935 | 0.227 | 0.000 | -6.445 | Likely Benign | 0.234 | Likely Benign | Likely Benign | 1.17 | Ambiguous | 0.1 | 0.54 | Ambiguous | 0.86 | Ambiguous | 0.88 | Ambiguous | 0.187 | Likely Benign | -1.07 | Neutral | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.39 | Benign | 0.46 | Tolerated | 0.1281 | 0.0860 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1292T>A | L431Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L431Q resides in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL and FATHMM; all other evaluated algorithms—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions or stability results are missing or inconclusive. Based on the overwhelming agreement among pathogenic predictions and the high‑accuracy tools, the variant is most likely pathogenic; this conclusion is not contradicted by ClinVar status, which is currently absent. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.094817 | Structured | 0.374755 | Uncertain | 0.959 | 0.300 | 0.000 | -12.399 | Likely Pathogenic | 0.986 | Likely Pathogenic | Likely Pathogenic | 2.69 | Destabilizing | 0.0 | 2.37 | Destabilizing | 2.53 | Destabilizing | 1.99 | Destabilizing | 0.493 | Likely Benign | -5.40 | Deleterious | 1.000 | Probably Damaging | 0.992 | Probably Damaging | 2.92 | Benign | 0.01 | Affected | 0.1036 | 0.1088 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1316T>A | L439Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L439Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.222385 | Structured | 0.281542 | Uncertain | 0.942 | 0.265 | 0.000 | -11.162 | Likely Pathogenic | 0.972 | Likely Pathogenic | Likely Pathogenic | 2.50 | Destabilizing | 0.1 | 2.06 | Destabilizing | 2.28 | Destabilizing | 1.35 | Destabilizing | 0.575 | Likely Pathogenic | -5.15 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.21 | Benign | 0.01 | Affected | 0.1065 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1352T>A | L451Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L451Q is not reported in ClinVar and is absent from gnomAD. Prediction tools uniformly indicate a deleterious effect: pathogenic predictions are returned by REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign outcome. High‑accuracy assessments reinforce this view: AlphaMissense‑Optimized classifies the change as pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, labels it likely pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, also reports a pathogenic effect. Consequently, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.281712 | Structured | 0.314017 | Uncertain | 0.978 | 0.232 | 0.000 | -15.426 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.0 | 2.48 | Destabilizing | 2.70 | Destabilizing | 2.30 | Destabilizing | 0.708 | Likely Pathogenic | -5.79 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.43 | Pathogenic | 0.00 | Affected | 0.0869 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1364T>A | L455Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L455Q is not reported in ClinVar (ClinVar status: none) and is absent from gnomAD (gnomAD ID: none). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact. High‑accuracy assessments further support this: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) also predicts pathogenic. No predictions are missing or inconclusive. Based on the overwhelming agreement among these tools, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation, as none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.188120 | Structured | 0.310377 | Uncertain | 0.963 | 0.168 | 0.000 | -13.075 | Likely Pathogenic | 0.997 | Likely Pathogenic | Likely Pathogenic | 2.84 | Destabilizing | 0.0 | 3.42 | Destabilizing | 3.13 | Destabilizing | 2.24 | Destabilizing | 0.655 | Likely Pathogenic | -5.66 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.23 | Benign | 0.00 | Affected | 0.0871 | 0.0958 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1499T>A | L500Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L500Q has no ClinVar entry and is not reported in gnomAD. Prediction tools that agree on a benign effect include only AlphaMissense‑Optimized. All other evaluated predictors—SGM‑Consensus, REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, and AlphaMissense‑Default—consistently classify the variant as pathogenic. FoldX, Rosetta, and Foldetta provide uncertain or inconclusive stability results and are treated as unavailable. High‑accuracy assessments further clarify the picture: AlphaMissense‑Optimized (benign) stands alone, whereas the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, predicts pathogenic. Foldetta remains uncertain. Overall, the preponderance of evidence from multiple independent pathogenic predictors indicates that the variant is most likely pathogenic, and this conclusion does not contradict ClinVar status, which currently has no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.066181 | Structured | 0.382942 | Uncertain | 0.893 | 0.150 | 0.000 | -13.431 | Likely Pathogenic | 0.649 | Likely Pathogenic | Likely Benign | 1.92 | Ambiguous | 0.1 | 1.78 | Ambiguous | 1.85 | Ambiguous | 1.49 | Destabilizing | 0.878 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.35 | Pathogenic | 0.00 | Affected | 0.0950 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1550T>A | L517Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L517Q is not reported in ClinVar and is absent from gnomAD, indicating no known population frequency data. Prediction tools that assess pathogenicity unanimously classify the variant as deleterious: SGM‑Consensus (Likely Pathogenic), REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. No tool predicts a benign effect, so the benign group is empty. High‑accuracy methods reinforce this view: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. All available evidence points to a pathogenic impact. Thus, the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar status because the variant is not yet catalogued there. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.147645 | Uncertain | 0.938 | 0.296 | 0.000 | -11.660 | Likely Pathogenic | 0.995 | Likely Pathogenic | Likely Pathogenic | 2.17 | Destabilizing | 0.1 | 2.07 | Destabilizing | 2.12 | Destabilizing | 1.87 | Destabilizing | 0.946 | Likely Pathogenic | -5.71 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.50 | Pathogenic | 0.00 | Affected | 0.1031 | 0.0888 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1628T>A | L543Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L543Q is not reported in ClinVar (ClinVar status: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that assess pathogenicity all agree on a deleterious effect: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized all classify the variant as pathogenic. No tool predicts a benign outcome. High‑accuracy methods reinforce this consensus: AlphaMissense‑Optimized predicts pathogenicity; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) also predicts pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta stability calculations, indicates a destabilizing, pathogenic effect. All available predictions are concordant and supportive. Therefore, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.020918 | Uncertain | 0.963 | 0.314 | 0.000 | -14.851 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 3.03 | Destabilizing | 0.2 | 3.48 | Destabilizing | 3.26 | Destabilizing | 2.25 | Destabilizing | 0.746 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.89 | Pathogenic | 0.00 | Affected | 0.0983 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1652T>A | L551Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L551Q is not reported in ClinVar and is present in gnomAD (allele ID 6‑33438895‑T‑A). In silico prediction tools uniformly indicate a deleterious effect: benign‑predicting tools: none; pathogenic‑predicting tools: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, FATHMM, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No predictions are inconclusive or missing. **Thus, the variant is most likely pathogenic based on the available predictions, and this conclusion does not contradict the ClinVar status (no entry).** Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.009977 | Structured | 0.006653 | Uncertain | 0.960 | 0.254 | 0.000 | 6-33438895-T-A | 1 | 6.20e-7 | -13.632 | Likely Pathogenic | 0.990 | Likely Pathogenic | Likely Pathogenic | 2.48 | Destabilizing | 0.1 | 2.19 | Destabilizing | 2.34 | Destabilizing | 2.37 | Destabilizing | 0.936 | Likely Pathogenic | -3.68 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | -1.60 | Pathogenic | 0.01 | Affected | 3.37 | 35 | 0.0983 | 0.0688 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||
| c.167T>A | L56Q 2D AIThe SynGAP1 missense variant L56Q is not reported in ClinVar (ClinVar ID = None) and is absent from gnomAD (gnomAD ID = None). Prediction tools that agree on a benign effect include REVEL, PROVEAN, and FATHMM. Tools that agree on a pathogenic effect include polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, and AlphaMissense‑Default. High‑accuracy assessments are mixed: AlphaMissense‑Optimized is uncertain; the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is inconclusive (2 pathogenic vs 2 benign), and Foldetta results are unavailable. Overall, the majority of available predictions (5 pathogenic vs 3 benign) indicate a pathogenic impact. There is no ClinVar entry to contradict this assessment, so the variant is most likely pathogenic. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | 0.342579 | Structured | 0.476218 | Uncertain | 0.495 | 0.657 | 0.000 | -11.064 | Likely Pathogenic | 0.926 | Likely Pathogenic | Ambiguous | 0.293 | Likely Benign | -2.03 | Neutral | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.79 | Benign | 0.00 | Affected | 0.1083 | 0.0842 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||||||||
| c.1694T>A | L565Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L565Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include only FATHMM, whereas the remaining tools—SGM‑Consensus, REVEL, FoldX, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—consistently predict a pathogenic or likely pathogenic impact; Rosetta is uncertain. High‑accuracy methods give the following results: AlphaMissense‑Optimized predicts pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) indicates likely pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or stability result is missing or inconclusive. Based on the overwhelming agreement among pathogenic predictors and the high‑accuracy tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.034884 | Structured | 0.045819 | Uncertain | 0.922 | 0.205 | 0.000 | -13.912 | Likely Pathogenic | 0.996 | Likely Pathogenic | Likely Pathogenic | 2.86 | Destabilizing | 0.1 | 1.95 | Ambiguous | 2.41 | Destabilizing | 2.39 | Destabilizing | 0.545 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.76 | Benign | 0.00 | Affected | 0.1149 | 0.0972 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1721T>A | L574Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L574Q resides in the GAP domain. ClinVar contains no entry for this variant, and it is not reported in gnomAD. Prediction tools that agree on a benign effect include REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic outcome are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and FATHMM; Rosetta’s assessment is uncertain. High‑accuracy methods give a consistent benign signal: 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 preponderance of evidence, the variant is most likely benign, and this assessment does not contradict any ClinVar status (none reported). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.083462 | Structured | 0.026427 | Uncertain | 0.927 | 0.246 | 0.000 | -3.015 | Likely Benign | 0.196 | Likely Benign | Likely Benign | 0.26 | Likely Benign | 0.2 | 0.52 | Ambiguous | 0.39 | Likely Benign | -0.18 | Likely Benign | 0.327 | Likely Benign | 2.53 | Neutral | 0.998 | Probably Damaging | 0.937 | Probably Damaging | -1.17 | Pathogenic | 0.65 | Tolerated | 0.1107 | 0.0888 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.176T>A | L59Q 2D AIThe SynGAP1 missense variant L59Q is not reported in ClinVar and is absent from gnomAD. Consensus predictions from multiple in‑silico tools are mixed: benign calls come from SGM‑Consensus (Likely Benign), REVEL, PROVEAN, ESM1b, and FATHMM, whereas pathogenic calls are made by polyPhen‑2 (HumDiv and HumVar), SIFT, AlphaMissense‑Default, and AlphaMissense‑Optimized. High‑accuracy assessments further highlight this discordance: AlphaMissense‑Optimized predicts a pathogenic effect, while the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates a likely benign outcome. No Foldetta stability analysis is available for this residue. Overall, the majority of high‑confidence tools lean toward a pathogenic interpretation, but the presence of several strong benign predictions and the lack of ClinVar evidence suggest uncertainty. The variant is most likely pathogenic based on the prevailing predictions, and this does not contradict any ClinVar annotation because none exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.212910 | Structured | 0.484882 | Uncertain | 0.510 | 0.668 | 0.000 | -3.841 | Likely Benign | 0.977 | Likely Pathogenic | Likely Pathogenic | 0.287 | Likely Benign | -2.21 | Neutral | 0.943 | Possibly Damaging | 0.944 | Probably Damaging | 3.26 | Benign | 0.00 | Affected | 0.1103 | 0.0758 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.1784T>A | L595Q 2D 3DClick to see structure in 3D Viewer AISynGAP1 missense variant L595Q is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized—predict a pathogenic effect, and the SGM‑Consensus score indicates a likely pathogenic outcome. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized returns a pathogenic prediction, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) also yields a likely pathogenic result, while Foldetta’s stability analysis is inconclusive. Overall, the majority of computational evidence points to a pathogenic effect, which does not contradict the ClinVar designation of uncertain significance but suggests a higher likelihood of pathogenicity. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.015344 | Structured | 0.128444 | Uncertain | 0.920 | 0.150 | 0.000 | Uncertain | 1 | -15.101 | Likely Pathogenic | 0.984 | Likely Pathogenic | Likely Pathogenic | 0.79 | Ambiguous | 0.1 | 1.40 | Ambiguous | 1.10 | Ambiguous | 1.99 | Destabilizing | 0.733 | Likely Pathogenic | -5.97 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.75 | Benign | 0.00 | Affected | 3.37 | 35 | 0.1074 | 0.1563 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.1898T>A | L633Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L633Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include only FATHMM, whereas all other evaluated algorithms—SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—classify the variant as pathogenic. High‑accuracy methods further support a deleterious impact: AlphaMissense‑Optimized predicts pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. No prediction or folding stability result is missing or inconclusive. Based on the overwhelming consensus of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because the variant is not yet catalogued in ClinVar. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.045352 | Structured | 0.045407 | Uncertain | 0.952 | 0.252 | 0.000 | -14.303 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.98 | Destabilizing | 0.1 | 2.97 | Destabilizing | 2.98 | Destabilizing | 2.23 | Destabilizing | 0.712 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 2.69 | Benign | 0.00 | Affected | 0.1333 | 0.0876 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1937T>A | L646Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense change L646Q lies in the GAP domain. ClinVar has no entry for this variant, and it is not present in gnomAD. Prediction tools that agree on a benign effect are REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated algorithms—FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and the SGM‑Consensus—classify the variant as pathogenic. High‑accuracy assessments further support a deleterious impact: AlphaMissense‑Optimized predicts benign, the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts pathogenic. Taken together, the overwhelming majority of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict the ClinVar status, which is currently unreported. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.048328 | Structured | 0.303751 | Uncertain | 0.941 | 0.344 | 0.000 | -12.735 | Likely Pathogenic | 0.752 | Likely Pathogenic | Likely Benign | 3.23 | Destabilizing | 0.1 | 3.04 | Destabilizing | 3.14 | Destabilizing | 2.12 | Destabilizing | 0.462 | Likely Benign | -2.78 | Deleterious | 0.994 | Probably Damaging | 0.790 | Possibly Damaging | 3.17 | Benign | 0.00 | Affected | 0.2090 | 0.1963 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1958T>A | L653Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L653Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that assess pathogenicity largely agree: SGM‑Consensus, REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (both HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized all predict a deleterious effect. Only FATHMM predicts a benign outcome. High‑accuracy methods reinforce the pathogenic signal: AlphaMissense‑Optimized is pathogenic, the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) is likely pathogenic, and Foldetta (combining FoldX‑MD and Rosetta) is pathogenic. No predictions are missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status (none is available). Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.049374 | Structured | 0.335213 | Uncertain | 0.963 | 0.332 | 0.000 | -14.347 | Likely Pathogenic | 0.993 | Likely Pathogenic | Likely Pathogenic | 2.71 | Destabilizing | 0.1 | 3.26 | Destabilizing | 2.99 | Destabilizing | 1.98 | Destabilizing | 0.614 | Likely Pathogenic | -5.65 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.09 | Benign | 0.01 | Affected | 0.1195 | 0.1363 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.1964T>A | L655Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L655Q is listed in ClinVar with an uncertain significance and is not reported in gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) all indicate benign or likely benign. Only the two polyPhen‑2 implementations (HumDiv and HumVar) predict pathogenicity, while Rosetta remains inconclusive. High‑accuracy assessments reinforce the benign consensus: AlphaMissense‑Optimized scores benign, the SGM‑Consensus is likely benign, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts benign stability. Overall, the majority of evidence supports a benign impact for L655Q, which does not contradict the ClinVar uncertain status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.015344 | Structured | 0.268808 | Uncertain | 0.961 | 0.274 | 0.000 | Uncertain | 1 | -5.278 | Likely Benign | 0.144 | Likely Benign | Likely Benign | -0.01 | Likely Benign | 0.0 | 0.69 | Ambiguous | 0.34 | Likely Benign | -0.15 | Likely Benign | 0.139 | Likely Benign | 0.61 | Neutral | 0.955 | Possibly Damaging | 0.602 | Possibly Damaging | 3.59 | Benign | 0.65 | Tolerated | 3.39 | 24 | 0.1248 | 0.0972 | -2 | -2 | -7.3 | 14.97 | 229.9 | -8.6 | 0.0 | 0.0 | 0.4 | 0.0 | X | Potentially Benign | The iso-butyl side chain of Leu655, located on the surface of an α helix (res. Ser641-Glu666), is not involved in any interactions in the WT simulations. In the variant simulations, the carboxamide side chain of Gln655 dynamically interacts with neighboring residues (e.g., Glu651, Glu656, Arg544) on the protein surface, with no negative structural effects. | ||||||||||||||||
| c.2009T>A | L670Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L670Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, PROVEAN, SIFT, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, and ESM1b. Predictions that are inconclusive (FoldX, Rosetta, Foldetta, premPS) are treated as unavailable. High‑accuracy assessments show AlphaMissense‑Optimized as benign, the SGM‑Consensus also as Likely Benign, while Foldetta remains uncertain. Overall, the majority of available evidence points to a benign impact. This conclusion is not contradicted by ClinVar, which contains no classification for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | GAP | 0.161087 | Structured | 0.090855 | Uncertain | 0.812 | 0.385 | 0.000 | -8.217 | Likely Pathogenic | 0.306 | Likely Benign | Likely Benign | 1.02 | Ambiguous | 0.1 | 1.21 | Ambiguous | 1.12 | Ambiguous | 0.96 | Ambiguous | 0.152 | Likely Benign | -1.12 | Neutral | 1.000 | Probably Damaging | 0.988 | Probably Damaging | 3.40 | Benign | 0.36 | Tolerated | 0.1088 | 0.1303 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.200T>A | L67Q 2D AIThe SynGAP1 missense variant L67Q is not reported in ClinVar (no ClinVar ID) and is absent from gnomAD (no gnomAD ID). Prediction tools that agree on a benign effect include REVEL, PROVEAN, ESM1b, FATHMM, AlphaMissense‑Optimized, and the SGM‑Consensus (Likely Benign). Tools that predict a pathogenic effect are polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. High‑accuracy assessments show AlphaMissense‑Optimized as benign and the SGM‑Consensus as Likely Benign; Foldetta results are not available. Overall, the majority of evidence points to a benign impact. This conclusion is consistent with the lack of ClinVar annotation, so there is no contradiction with existing clinical data. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Benign | 0.458154 | Structured | 0.473668 | Uncertain | 0.428 | 0.761 | 0.125 | -3.948 | Likely Benign | 0.687 | Likely Pathogenic | Likely Benign | 0.115 | Likely Benign | -0.66 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.10 | Benign | 0.00 | Affected | 0.0861 | 0.0719 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||||||||||||
| c.2018T>A | L673Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L673Q is not reported in ClinVar (ClinVar ID None) and is absent from gnomAD (gnomAD ID None). Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. Tools that agree on a pathogenic effect include Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, and ESM1b. FoldX and Foldetta, as well as AlphaMissense‑Default, are inconclusive and are treated as unavailable evidence. High‑accuracy assessments show AlphaMissense‑Optimized predicting benign, while the SGM Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) predicts pathogenic. Foldetta remains uncertain. Overall, the majority of available predictions (seven pathogenic vs. three benign) indicate that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because no ClinVar claim exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | GAP | 0.060549 | Structured | 0.104692 | Uncertain | 0.545 | 0.369 | 0.000 | -11.963 | Likely Pathogenic | 0.445 | Ambiguous | Likely Benign | 1.56 | Ambiguous | 0.2 | 2.32 | Destabilizing | 1.94 | Ambiguous | 1.02 | Destabilizing | 0.190 | Likely Benign | -3.40 | Deleterious | 1.000 | Probably Damaging | 0.968 | Probably Damaging | 3.32 | Benign | 0.03 | Affected | 0.1045 | 0.1172 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||
| c.203T>A | L68Q 2D AIThe SynGAP1 missense variant L68Q is listed in gnomAD (6‑33425811‑T‑A) but has no ClinVar entry. Functional prediction tools cluster into two groups: benign predictions from REVEL, PROVEAN, ESM1b, and FATHMM; pathogenic predictions from polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, and AlphaMissense‑Default. The SGM‑Consensus, which aggregates AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, reports a likely benign outcome, reflecting the majority of benign calls. High‑accuracy assessments are limited: AlphaMissense‑Optimized is uncertain, and Foldetta results are not available. Based on the available evidence, 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 | 0.470567 | Uncertain | 0.405 | 0.768 | 0.250 | 6-33425811-T-A | 5 | 3.10e-6 | -3.436 | Likely Benign | 0.826 | Likely Pathogenic | Ambiguous | 0.119 | Likely Benign | -0.14 | Neutral | 0.943 | Possibly Damaging | 0.766 | Possibly Damaging | 4.15 | Benign | 0.00 | Affected | 4.32 | 1 | 0.0864 | 0.0919 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||||||
| c.2075T>A | L692Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L692Q is listed in ClinVar as Pathogenic (ClinVar ID 2714634.0) and is not reported in gnomAD. Prediction tools that classify the variant as benign include only FATHMM. All other evaluated algorithms—REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic effect. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus, derived from a majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN, is pathogenic; and Foldetta, which integrates FoldX‑MD and Rosetta outputs, is pathogenic. No prediction or stability result is missing or inconclusive. Based on the consensus of these tools, the variant is most likely pathogenic, and this conclusion aligns with its ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.064632 | Structured | 0.295225 | Uncertain | 0.966 | 0.243 | 0.000 | Pathogenic | 1 | -13.873 | Likely Pathogenic | 0.998 | Likely Pathogenic | Likely Pathogenic | 3.24 | Destabilizing | 0.1 | 3.27 | Destabilizing | 3.26 | Destabilizing | 2.76 | Destabilizing | 0.596 | Likely Pathogenic | -5.98 | Deleterious | 1.000 | Probably Damaging | 0.998 | Probably Damaging | 3.06 | Benign | 0.00 | Affected | 3.42 | 17 | 0.1079 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||
| c.2084T>A | L695Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L695Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect include SIFT, FATHMM, and AlphaMissense‑Optimized. Those that predict a pathogenic impact comprise REVEL, Rosetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), ESM1b, AlphaMissense‑Default, and the SGM‑Consensus (majority vote from AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). FoldX and Foldetta provide uncertain results. High‑accuracy assessments show AlphaMissense‑Optimized as benign, while the SGM‑Consensus, derived from a majority of high‑confidence predictors, indicates pathogenicity; Foldetta remains inconclusive. Overall, the majority of reliable tools predict a pathogenic effect, and this is consistent with the lack of ClinVar annotation (no contradiction). Thus, the variant is most likely pathogenic based on current computational predictions. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.118441 | Structured | 0.373419 | Uncertain | 0.942 | 0.258 | 0.000 | -12.192 | Likely Pathogenic | 0.706 | Likely Pathogenic | Likely Benign | 1.88 | Ambiguous | 0.1 | 2.03 | Destabilizing | 1.96 | Ambiguous | 1.71 | Destabilizing | 0.554 | Likely Pathogenic | -5.92 | Deleterious | 1.000 | Probably Damaging | 0.993 | Probably Damaging | 3.17 | Benign | 0.08 | Tolerated | 0.0869 | 0.0688 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2099T>A | L700Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L700Q is not reported in ClinVar and has no entry in gnomAD. Prediction tools that agree on a benign effect include REVEL, FATHMM, and AlphaMissense‑Optimized. All other evaluated tools—SGM‑Consensus, FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, and AlphaMissense‑Default—predict a pathogenic impact. High‑accuracy methods give a mixed picture: AlphaMissense‑Optimized indicates a benign change, whereas the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) and Foldetta (combining FoldX‑MD and Rosetta outputs) both predict pathogenicity. No predictions are missing or inconclusive. Overall, the preponderance of evidence from the majority of tools points to a pathogenic effect, and this assessment does not contradict any ClinVar status because none is available. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.113710 | Structured | 0.416255 | Uncertain | 0.927 | 0.331 | 0.000 | -10.522 | Likely Pathogenic | 0.783 | Likely Pathogenic | Likely Benign | 2.41 | Destabilizing | 0.1 | 4.02 | Destabilizing | 3.22 | Destabilizing | 1.35 | Destabilizing | 0.321 | Likely Benign | -3.79 | Deleterious | 0.994 | Probably Damaging | 0.896 | Possibly Damaging | 3.34 | Benign | 0.01 | Affected | 0.1074 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2126T>A | L709Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L709Q is not reported in ClinVar and is absent from gnomAD. Functional prediction tools largely agree on a benign effect: REVEL, FoldX, Rosetta, Foldetta, premPS, PROVEAN, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, AlphaMissense‑Optimized, and the SGM‑Consensus (majority vote) all indicate benign or likely benign. Only two tools, polyPhen‑2 HumDiv and HumVar, 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) predicts benign stability. Thus, 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 | GAP | 0.243554 | Structured | 0.365830 | Uncertain | 0.934 | 0.379 | 0.000 | -5.758 | Likely Benign | 0.179 | Likely Benign | Likely Benign | 0.13 | Likely Benign | 0.0 | 0.40 | Likely Benign | 0.27 | Likely Benign | 0.18 | Likely Benign | 0.033 | Likely Benign | -0.78 | Neutral | 0.998 | Probably Damaging | 0.923 | Probably Damaging | 3.52 | Benign | 0.48 | Tolerated | 0.0838 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2132T>A | L711Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L711Q is not reported in ClinVar (ClinVar ID: None) and is absent from gnomAD (gnomAD ID: None). Prediction tools that agree on a benign effect are REVEL and FATHMM. Tools that predict a pathogenic effect include FoldX, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, AlphaMissense‑Optimized, SGM Consensus, and Foldetta; Rosetta is uncertain. High‑accuracy methods give a consistent pathogenic signal: AlphaMissense‑Optimized predicts Pathogenic, SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN) indicates Likely Pathogenic, and Foldetta (combining FoldX‑MD and Rosetta outputs) predicts Pathogenic. No predictions are missing or inconclusive. Based on the preponderance of pathogenic predictions, the variant is most likely pathogenic, and this assessment does not contradict any ClinVar status because no ClinVar entry exists. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.308712 | Structured | 0.377436 | Uncertain | 0.950 | 0.364 | 0.000 | -11.792 | Likely Pathogenic | 0.994 | Likely Pathogenic | Likely Pathogenic | 2.93 | Destabilizing | 0.0 | 1.68 | Ambiguous | 2.31 | Destabilizing | 1.63 | Destabilizing | 0.388 | Likely Benign | -5.67 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.31 | Benign | 0.00 | Affected | 0.1041 | 0.0488 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2141T>A | L714Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L714Q is not reported in ClinVar (ClinVar: not reported) and is absent from gnomAD (gnomAD: not found). Prediction tools that agree on a benign effect are REVEL and FATHMM. All other evaluated tools—including FoldX, Rosetta, Foldetta, premPS, PROVEAN, polyPhen‑2 (HumDiv and HumVar), SIFT, ESM1b, AlphaMissense‑Default, and AlphaMissense‑Optimized—predict a pathogenic impact. High‑accuracy assessments further support pathogenicity: AlphaMissense‑Optimized is pathogenic; the SGM Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, and PROVEAN) is Likely Pathogenic; and Foldetta (combining FoldX‑MD and Rosetta outputs) is pathogenic. No predictions are missing or inconclusive. Overall, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion is not contradicted by the current ClinVar status. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | GAP | 0.314870 | Structured | 0.402311 | Uncertain | 0.961 | 0.369 | 0.000 | -12.145 | Likely Pathogenic | 0.999 | Likely Pathogenic | Likely Pathogenic | 2.91 | Destabilizing | 0.0 | 5.23 | Destabilizing | 4.07 | Destabilizing | 2.13 | Destabilizing | 0.378 | Likely Benign | -5.56 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 3.11 | Benign | 0.00 | Affected | 0.1096 | 0.0558 | -2 | -2 | -7.3 | 14.97 | |||||||||||||||||||||||||||||
| c.2174T>A | L725Q 2D 3DClick to see structure in 3D Viewer AIThe SynGAP1 missense variant L725Q is not reported in ClinVar and is absent from gnomAD. Prediction tools that agree on a benign effect are limited to REVEL, which scores the variant as benign. The majority of tools predict a pathogenic impact: premPS, PROVEAN, polyPhen‑2 HumDiv, polyPhen‑2 HumVar, SIFT, ESM1b, FATHMM, AlphaMissense‑Default, Rosetta, and the SGM‑Consensus (majority vote of AlphaMissense‑Default, ESM1b, FATHMM, PROVEAN). Uncertain or inconclusive results come from FoldX, Foldetta, and AlphaMissense‑Optimized. High‑accuracy assessments show AlphaMissense‑Optimized as uncertain, SGM‑Consensus as likely pathogenic, and Foldetta as uncertain. Taken together, the preponderance of evidence indicates that the variant is most likely pathogenic, and this conclusion does not contradict any ClinVar annotation because none exists for this variant. Disclaimer: This summary was generated using AI and should be interpreted alongside expert review. | Likely Pathogenic | 0.557691 | Disordered | 0.455613 | Uncertain | 0.911 | 0.491 | 0.625 | -13.952 | Likely Pathogenic | 0.888 | Likely Pathogenic | Ambiguous | 1.55 | Ambiguous | 0.1 | 2.09 | Destabilizing | 1.82 | Ambiguous | 1.88 | Destabilizing | 0.319 | Likely Benign | -5.43 | Deleterious | 1.000 | Probably Damaging | 1.000 | Probably Damaging | 1.28 | Pathogenic | 0.00 | Affected | 0.1198 | 0.1203 | -2 | -2 | -7.3 | 14.97 | ||||||||||||||||||||||||||||||
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